Printer Friendly

Neuroecology, chemical defense, and the keystone species concept.

Introduction

A wide range of critical ecological interactions are mediated by chemistry. Biological responses to environmental chemical stimuli abound. Sensory perception of chemical signals, for example, strongly influences predation (Nevitt et al., 1995; Zimmer-Faust et al., 1995; Baldwin et al., 2006), courtship and mating (Dussourd et al., 1991; Painter et al., 1998; Bray and Amrein, 2003; Johnston, 2003; Riffell et al., 2004), aggregation and school formation (Blackburn et al., 1998; Keeling et al., 2003), and habitat colonization (Zimmer-Faust and Tamburri, 1994; Swanson et al., 2004; Lecchini et al., 2005; Dreanno et al., 2006). Additionally, chemical defenses produced by prey organisms (animals, plant, and microbes) render their tissues unpalatable or toxic to consumers (Whittaker and Feeny, 1971; Janzen, 1977; Lindquist and Hay, 1996; Nagle and Paul, 1998; Cruz-Rivera and Villareal, 2006). Despite the crucial ecological importance of such molecules, underlying mechanisms are lacking for most processes that structure communities. Natural products chemistry and chemical ecology have emphasized studies of secondary metabolites acting as toxins and antifeedants (Hay and Fenical, 1988; Pawlik, 1993; Daly, 1995; McClintock and Baker, 1997; Eisner et al., 2000). Yet there are numerous outstanding examples of secondary metabolites serving multiple roles and regulating the behavioral or physiological responses of individuals at lower trophic levels (Weller et al., 1999; Arnold and Targett, 2002; Bernays et al., 2002a, b; Camacho and Thacker, 2006; Steinke et al., 2006). Transferred to consumers at higher trophic levels, these effects have profound consequences for the distributions and abundances of organisms.

Unifying principles in ecology can provide conceptual frameworks for chemical defense and signaling. Optimal defense theory, Jensen's inequality, and the growth-differentiation balance hypothesis are benchmark intellectual achievements in chemical ecology, with roots embedded in a larger ecological context (McKey, 1974; Rhodes and Cates, 1976; Herms and Mattson, 1992; Ruel and Ayers, 1999). Similarly, the "keystone" species concept is intrinsically valuable for directing research and integrating studies on chemical defenses, chemosensory systems, behavior, and population and community dynamics.

A keystone species is one whose impacts on a community are greater than would be predicted from its relative abundance or total biomass (Paine, 1966; Estes and Duggins, 1995; Power et al., 1996; Menge et al., 2004). Sea otters (Enhydra lutris), for example, are carnivores in giant kelp forests of the northeast Pacific Ocean. Although their population densities are low, their predation on herbivores drastically reduces grazing pressure on kelp, leading to a highly diverse community of plants and associated invertebrate and fish species (Estes and Duggins, 1995; Steinberg et al., 1995). Removal of otters from kelp forest habitats, in contrast, facilitates herbivore survivorship and reproduction, accelerating grazing pressure and resulting in barren grounds as an alternative, stable community state (Estes and Palmisano, 1974; Duggins et al., 1989). Red-banded newts (Notophthalmus viridescens) similarly have dramatic effects in streams of the southeastern United States. Foraging by naturally small populations of these salamanders impacts composite community attributes, including species diversity and total prey biomass (Kurzava and Morin, 1998; Davic and Welsh, 2004; Smith, 2006). Moreover, newt predation significantly affects both vertebrate and invertebrate communities in the water column and on the stream bed. Grizzly bears (Ursus arctos) and beavers (Castor canadensis) are also keystone species, although the ways in which they modify community dynamics differ from those of otters and newts: bears alter rates of material (primarily nitrogen) exchange between aquatic and terrestrial environments, and beavers restructure physical habitats (Jones et al., 1994, 1997; Hilderbrand et al., 1999; Helfield and Naiman, 2006).

Neurotoxins are rare within natural communities, but they exert profound effects on species interactions at multiple trophic levels and thus could function in keystone roles (Williams et al., 2004; Ferrer and Zimmer, 2007a, b). The guanidine alkaloids, in particular, compose some of the most potent natural poisons ever described, with devastating effects as feeding deterrents at extremely dilute concentrations. Toxin-mediated processes that inhibit the generation of action potentials in nerve and muscle tissues are well understood at molecular and cellular levels (Noda et al., 1989; Terlau et al., 1991; Satin et al., 1992; Cestele and Catterall, 2000). These toxins also affect trophic interactions, biomagnification, and evolved resistances in higher order consumer species (Brodie and Brodie, 1990; Llewellyn, 1997; Kvitek and Bretz, 2004; Williams et al., 2004; Bricelj et al., 2005; Llewellyn et al., 2006). Few investigations have connected the dots, however, for vertically integrating neural effects and ecological consequences at individual, population, and community levels. Such is the purpose of this synthesis on neuroecology, chemical defense, and the keystone species concept.

Here, the guanidine alkaloids tetrodotoxin (TTX) and saxitoxin (STX) are used to illustrate recent research findings that coalesce neurobiological and ecological paradigms. We know more about the integrative biology of these toxins than about any other poison. Each of our examples begins with a brief explanation of the cellular principles underlying toxicity. Next, we consider the ecological consequences of each toxin and focus specifically on their realized, as well as hypothesized, roles in mediating trophic interactions and community dynamics. Such interactions are best understood, and therefore emphasized, for organisms living in riparian stream and coastal ocean environments.

Historically, TTX and STX were known as inhibitors of nerve and muscle function (Kao, 1966; Evans, 1972; Hille, 1975); contemporarily, we also know them as mediators of both chemical defense and chemical communication (Kvitek et al., 1991; Kvitek and Beitler, 1991; Daly, 1995; Matsumura, 1995; Hwang et al., 2004; Camacho and Thacker, 2006; Zimmer et al., 2006). The chemoreceptors of some species apparently evolved for toxin interactions that stimulate, rather than suppress, conduction of nerve impulses (Yamamori et al., 1988; Zimmer et al., 2006). This varied array of physiological effects, expressed differentially across many species, has community-wide impacts, ultimately rendering TTX and STX as keystone molecules of substantial ecological importance.

The Neuroecology of Chemical Defense in Riparian Communities: Tetrodotoxin and Arginine

Cellular basis for tetrodotoxin toxicity and chemical defense

Tetrodotoxin (TTX) is a heterocyclic guanidine alkaloid harbored naturally by microbes and metazoans of phylogenetically diverse origins (Fig. la; Kim et al., 1975; Sheumack et al., 1978; Miyazawa et al., 1986; Thuesen et al., 1988). This neurotoxin acts as a chemical defense by inhibiting the transmission of signals between electrically excitable cells in consumers, and thus inducing paralysis and respiratory failure (Li, 1963; Kao and Fuhrman, 1963; Brodie, 1968). The molecule binds specifically and with high affinity to voltage-gated sodium channels on membranes of nerve and muscle cells (Hille, 1975; Kao, 1986; Catterall, 1992). In normal, unaffected cells, action potentials are generated and propagated by the influx of extracellular sodium ions through voltage-gated sodium channels, leading to conduction of an electrical impulse (Hille, 1984; Catterall, 1988). Bound TTX blocks the transport of sodium ions through the channel, effectively eliminating depolarization and impulse transmission (Hille, 1975; Kao, 1986).

Mechanisms of TTX binding and the characterization of its receptor site have particular relevance to the structure and function of voltage-gated sodium channels (Fig. 2A). The major subunit of a sodium channel, the [alpha]-subunit, is composed of four homologous domains (DI-DIV), each having six transmembrane segments (S1-S6). The TTX binding site--toxin receptor site 1--is located on the extracellular side of the sodium channel protein at a pore loop (SS2) that connects segments S5 and S6 on each of the four domains (Terlau et al., 1991). Studies using site-directed mutagenesis of sodium channels from brain, skeletal muscle, and cardiac muscle have identified amino acid residues on the SS2 loop critical in TTX binding (Noda et al., 1989; Terlau et al., 1991; Backx et al., 1992; Satin et al., 1992; Penzotti et al., 1998). Positions 385 of domain I in brain sodium channels and 401 of domain I in skeletal muscle sodium channels consist of phenylalanine and tyrosine, respectively. These aromatic amino acids confer high TTX binding affinity, and thus sensitivity to the toxin, in brain and skeletal muscle tissues. Cardiac muscle, however, possesses a substituted cysteine at the analogous residue 374 and consequently reduces TTX sensitivity 100- to 1000-fold (Chen et al., 1992; Satin et al., 1992; Lipkind and Fozzard, 1994). Additionally, toxin binding is eliminated completely by neutralization of glutamic or aspartic acid residues thought to interact electrostatically with the guanidinium moiety of TTX (Noda et al., 1989: Terlau et al., 1991).

[FIGURE 1 OMITTED]

More specifically, the pore binding site is composed of two paired sets of important residues, each pair residing on the SS2 loops of domains I through IV. The four respective SS2 loops collectively form a binding pore, consisting of important inner and outer residue rings. The outer ring is composed of glutamic acid, glutamic acid, methionine, and aspartic acid from domains I-IV, respectively. In contrast, aspartic acid, glutamic acid, lysine, and alanine make up the inner ring of the binding pore and function as the DEKA selectivity filter of the channel. TTX binding at this inner ring, or mutation of any of these residues, eliminates ionic conductance (Terlau et al., 1991; Heinemann et al., 1992), suggesting that TTX physically occludes the channel and thus blocks ion influx. It does so by interacting with the receptor site through guanidinium and C9, C10, and C11 hydroxyl groups (Lipkind and Fozzard, 1994; Penzotti et al., 1998; Choudhary et al., 2003).

[FIGURE 2 OMITTED]

Ecology of tetrodotoxin chemical defense and resistance

When disturbed by predators, many amphibians secrete a variety of toxins, including TTX, from glands along their dorsum (for reviews, see Daly, 1995; Toledo and Jared, 1995). These compounds, and the animals that produce them, are critical components of freshwater and riparian communities. Newts of the genus Taricha are especially meaningful candidates for studies on neuroecology. They reside in freshwater ponds and streams along the west coast of North America, and they use TTX as a potent chemical defense during many stages in their life cycle (Buchwald et al., 1964; Hanifin et al., 2002, 2003).

When ingested, sufficiently high concentrations of TTX inhibit neuromuscular function, resulting in paralysis and death. These effects have been observed in a wide array of vertebrate carnivores (Brodie, 1968; McAllister et al., 1997; Mobley and Stidham, 2000). Although Taricha newts are chemically well defended by TTX, sympatric garter snakes of the genus Thamnophis have evolved a resistance to the compound (Brodie and Brodie, 1990, 1999; Brodie et al., 2005). The most tolerant snakes can eat many toxic newts in a short period of time (Brodie, 1968). Consequently, predation by garter snakes may significantly impact Taricha populations, particularly where habitat loss and other anthropogenic effects have already reduced newt densities (Jennings and Hayes, 1994; Riley et al., 2005).

The molecular basis for the immunity of garter snakes to toxic newts reveals phenotypic adaptation (Geffeney et al., 2002, 2005). TTX resistance in snake skeletal muscle arises from mutations altering amino acid residues on receptor-binding sites for voltage-gated, sodium channel proteins (Fig. 3A). A single amino acid substitution, from isoleucine to valine, at residue 1561 confers low levels of resistance. Conversely, snakes with high resistance have undergone mutations altering amino acid residues at as many as four separate sites (Geffeney et al., 2005). In fact, snake resistance to TTX has evolved independently in different populations through small changes in sodium channel sequences.

Ecological interactions at higher trophic levels also are affected by TTX. After garter snakes ingest poisonous newts, TTX accumulates in the tissues of the snakes for several weeks at concentrations within the lethal ranges of higher order predators (Williams et al., 2004). After a diet of newts, Thamnophis snakes--natural prey of many raptors--pose a threat to their predators. Furthermore, owls and waterfowl have been found dead with TTX-laden newts lodged in their esophageal tracts (Pimentel, 1952; McAllister et al., 1997; Mobley and Stidham, 2000). Mortality of these apex predators due to TTX consumption could generate cascading effects throughout freshwater and riparian communities.

[FIGURE 3 OMITTED]

Tetrodotoxin as a chemosensory cue of predation risk

Larval newts, unlike adults, juveniles, and embryos, are not chemically defended and are vulnerable to a number of vertebrate and invertebrate predators (Kats et al., 1992; Gamradt and Kats, 1996). Although TTX is absent from the skin of larvae, TTX released from adult newts is detected by larvae and stimulates predatory-avoidance and refuge-hiding behaviors (Table 1; Zimmer et al., 2006). Because aquatic adults exhibit intense cannibalism on larvae when the abundance of alternative prey is low, TTX is a reliable indicator of predation threat and alerts young newts to seek refuge. Once larvae visually detect a refuge, they move rapidly and on a linear trajectory to a hiding place. From the point of TTX contact, they swim directionally, upstream or downstream depending on the location of the refuge; thus the behavior is not simply an aversive reaction to a noxious chemical (Zimmer et al., 2006). Hence, TTX plays a dual role in freshwater habitats, serving both as a chemical defense and a predator-avoidance cue.

Electrophysiological assays in complement with behavioral experiments on newt larvae demonstrate the role of olfaction in mediating predator avoidance. Olfactory receptor cells of the larvae are excited by applications of TTX at 1 [micro]mol [l.sup.-1] (or lower), and refuge-hiding behavior is evoked by TTX at concentrations as dilute as 1 nmol [l.sup.-1] (Fig. 4A; Zimmer et al., 2006). Whereas larvae perceive TTX emitted from cannibalistic adult newts as olfactory information, they exhibit muscle tremors and morbidity when exposed to unnaturally high concentrations of the toxin (at and above 10 [micro]mol [l.sup.-1]). Such opposing physiological effects are dose-dependent, inhibiting or stimulating larval neuromotor activity at high or low concentrations, respectively. This disparity may arise because of differences in the TTX binding affinities for olfactory receptors (high) and voltage-gated sodium channels (low). In fact, protein sequences of sodium channels varying by even one amino acid residue express notably different TTX binding affinities among salamanders (Kaneko et al., 1997). Low binding affinity for sodium channel receptor sites, resulting in TTX resistance, allows animals to detect the alkaloid and respond behaviorally to dilute concentrations by using high-affinity, TTX-sensitive olfactory receptors. Therefore, in resistant organisms, TTX can convey chemosensory information that mediates trophic interactions.

[FIGURE 4 OMITTED]

Global significance of tetrodotoxin as a combined signal/defense molecule

Like newts, other organisms have evolved mechanisms for recognizing TTX as a source of information (Table 2). Male puffer fish, for example, are attracted to TTX after its emission from gravid females (Matsumura, 1995). Moreover, resistant carnivorous snails exhibit feeding attraction to TTX-laden prey, presumably as a means of sequestering the poison from a dietary source (Hwang et al., 2004). There is, however, no physiological evidence of the specific sensory mechanisms underlying these behaviors.

The community-wide consequences observed for TTX in riparian habitats await discovery in other systems. Pervasive effects of the molecule seem inevitable, because TTX has a nearly cosmopolitan biogeographical distribution within marine, freshwater, and terrestrial organisms (Kim et al., 1975; Sheumack et al., 1978; Miyazawa et al., 1986; Thuesen et al., 1988; Matsumura, 1995; Kogure et al., 1996; Ritson-Williams et al., 2006). Moreover, it functions globally as a chemical defense for prey, a predator venom to subdue prey, a predator-avoidance cue, and a sex pheromone. Such remarkable flexibility arises from the contrasting impacts of different chemical concentrations, and points to TTX as a bioactive molecule of considerable ecological significance.

Arginine as a chemosensory cue of reduced predation risk and as a feeding attractant

The basic amino acid arginine, structurally similar to TTX, has very different but equally critical effects on trophic relationships (Table 1 and Fig. 2D). As feeding generalists, adult Taricha torosa dine on a taxonomically diverse prey assemblage, including primarily insects, worms, snails, and other small invertebrates (Stebbins, 1972; Hanson et al., 1994; R. P. Ferrer and R. K. Zimmer, unpubl. data). When adult newts feed on invertebrate prey, arginine is released at elevated concentrations into surrounding stream water (Ferrer and Zimmer, 2007a). Arginine concentrations in amphibian tissues and blood are at least 10-20 times lower than those in stream invertebrates (Gallardo et al., 1994; Emelyanova et al., 2004). Consequently, arginine is much more likely to signal the presence of injured invertebrates than of larval conspecifics.

California newt adults feed preferentially on worms over conspecific young, and there is no evidence for adult adaptations specifically for cannibalism (Elliott et al., 1993; Kerby and Kats, 1998). The cannibal-avoidance response in larvae is therefore suppressed when arginine from injured invertebrate prey mixes with TTX from adults (Table 1; Ferrer and Zimmer, 2007b). Experimental results suggest that the guanidinium moiety, present on both arginine and TTX, is likely to compete for common chemoreceptor-binding sites (Fig. 2B). Hence, the presence of arginine signals a reduced predation threat, and mixture suppression decreases fitness costs by inhibiting antipredator behavior. In contrast, arginine released from damaged prey stimulates foraging behavior in adult newts (Table 1; Ferrer and Zimmer, 2007a). Attractant chemical plumes function as a road map for the adults to find prey, thus facilitating further predation on invertebrate populations.

TTX and its congener, arginine, tightly link trophic levels ranging from deposit feeders and detritivores, such as worms and aquatic insects, to apex predators including hawks and owls (Fig. 5). The predator-prey interactions that shape both vertebrate and invertebrate communities are mediated by these compounds due to their opposing roles. Whereas TTX defends adult newts and resistant garter snakes by inhibiting neuromuscular function in predators, the toxin stimulates olfactory receptor cells in larval newts, eliciting avoidance behavior and reducing predator-driven mortality. Conversely, arginine suppresses larval antipredator responses to TTX, while activating food search and feeding behavior in adults. Although olfactory, gustatory, and vomeronasal organs function throughout a newt's life-time, an ontogenetic shift in larval and adult chemosensory ability changes behavioral expression, hence reflecting the unique selection pressures that act at each life-history stage (Ferrer and Zimmer, 2007a,b).

[FIGURE 5 OMITTED]

The Neuroecology of Chemical Defense in Coastal Marine Communities: Saxitoxin

Cellular basis for saxitoxin toxicity and chemical defense

Communities within coastal marine habitats worldwide are shaped by phytoplankton chemical defenses. These molecules significantly modify material exchange rates among organisms in the water column, and between benthic and pelagic environments. The paralytic alkaloid saxitoxin (STX) is a potent neurotoxin synthesized by marine dinoflagellates (Fig. 1B; Schantz et al., 1966; Proctor et al., 1975; Bates et al., 1978; Shimizu, 1987) and certain freshwater cyanobacteria (Jackim and Gentile, 1968; Negri and Jones, 1995). During algal blooms, STX in surrounding waters can reach harmful concentrations, resulting in major die-offs of fish (White, 1980, 1981) and benthic invertebrates (Nagai et al., 2000; Yamatogi et al., 2005).

Like tetrodotoxin (TTX), STX is a heterocyclic guanidine alkaloid that binds with high affinity to sodium channel proteins and prevents the influx of sodium ions into excitable cells (Fig. 2A and D; Hille, 1975; Kao, 1986; Catterall, 1992; Lipkind and Fozzard, 1994). The two poisons are about the same size, with one or two positively charged guanidinium groups (Hille, 1975; Kao and Walker, 1982; Kao, 1986). They competitively inhibit each other in binding assays (Hansen-Bay and Strichartz, 1980; Sherman et al., 1983). Moreover, specific amino acid substitutions at toxin receptor site 1 of sodium channels produce similar effects on STX and TTX binding (Noda et al., 1989; Terlau et al., 1991; Kontis and Goldin, 1993). Thus, the two compounds are largely complementary in structure and function. Site-directed mutagenesis studies reveal that STX 7, 8, 9 and TTX 1, 2, 3 guanidinium groups each bind with an aspartic acid, glutamic acid, lysine, and alanine (DEKA) selectivity filter (at the inner region of the pore) of voltage-gated sodium channel proteins (Penzotti et al., 1998). Whereas TTX has a stronger interaction at amino acid residue 401 (tyrosine), STX interacts more effectively with the more extracellular residues. Unique moieties of each toxin are relegated to interactions with receptors at secondary binding sites on the SS2 loop. Ultimately, sodium ion influx into excitable cells is blocked principally by STX/TTX guanidinium interaction with the selectivity filter, despite subtle differences in toxin structures and sodium channel receptor associations.

Ecology of saxitoxin chemical defense and resistance

Dinoflagellate population growth can be tightly regulated by planktonic grazers and benthic, suspension-feeding invertebrates (Blasco, 1977; Turner and Anderson, 1983; Uye, 1986). Common consumers include ciliates (Stoecker et al., 1981), copepods and other zooplankton crustaceans (Fenchel, 1988), larval and adult fish (Last, 1980; Stoecker and Govoni, 1984; Gosselin et al., 1989; Robineau et al., 1991), and larval and adult macroinvertebrates (Robineau et al., 1991). In many cases, grazing pressure imposed by these organisms is significantly reduced when STX and related compounds are produced at high concentrations in dinoflagellates or cyanobacteria (Fiedler, 1982; Ives, 1985; Huntley et al., 1986; Haney et al., 1995; Marsden and Shumway, 1995; Smayda, 1997).

The physiological effects elicited by STX on its consumers vary among and within taxonomic groups. Vertebrates, such as fish, birds, and mammals, that take in STX exhibit loss of neuromuscular control, suppressed breathing, regurgitation, and abnormal behavior; in many cases, mortality results (White, 1981; Kvitek, 1991; Kvitek et al., 1991; Shumway et al., 2003). These effects are consistent with the selective inhibition of sodium ion influx associated with STX and TTX sodium channel binding (Li, 1963; Kao and Fuhrman, 1963). Grazing ciliates, however, undergo ciliary reversal, swelling, and cell lysis when exposed to STX (Hansen, 1989; Hansen et al., 1992). Furthermore, whereas some invertebrate grazers show decreases in consumption and swimming rates after ingesting STX (Ives, 1987; Sykes and Huntley, 1987; Haney et al., 1995), other closely related groups are unaffected (Teegarden and Cembella, 1996) or exhibit feeding stimulation by the toxin (Table 2). Changes in feeding rates can be attributed to chemosensory mechanisms (Huntley et al., 1986; Haney et al., 1995; Turriff et al., 1995; Teegarden and Cembella, 1996).

Many marine organisms are capable of accumulating STX in their tissues by consuming toxin-producing dinoflagellates (Twarog et al., 1972; Bricelj and Shumway, 1998; Turner et al., 2000; Llewellyn et al., 2006). The poison and its associated metabolites are present in a highly biodiverse assemblage of invertebrates, such as bivalves, gastropods, crustaceans, and echinoderms, in temperate (Jonas-Davies and Liston, 1985) and tropical waters (Llewellyn et al., 2006). Moreover, vertebrate predators, including several species of fish, also accumulate STX in their tissues, digestive tracts, and eggs (Nakamura et al., 1984; Llewellyn et al., 2006). The presence of these paralytic compounds in omnivores and carnivores indicates that they can be transferred among resistant consumers across multiple trophic levels and even to apex predators.

Although isolated and dinoflagellate-associated bacteria are capable of producing STX (Kodama et al., 1988, 1990; Gallacher et al., 1997; Baker et al., 2003), accumulation of the toxin in higher organisms occurs via dietary intake or exposure to surrounding toxin-laden waters during algal blooms (Schantz, 1986; Bricelj et al., 1990). This mechanism contrasts with that of most animals that sequester TTX through direct associations with bacterial symbionts (Noguchi et al., 1986; Ritchie et al., 2000). Select species with evolved resistance concentrate high doses of STX while maintaining normal nerve and muscle function (Kvitek and Beitler, 1991; Bricelj et al., 2005). Such resistance facilitates feeding on potentially poisonous prey, while borrowing the consumed toxin for their own chemical defense.

Immunity to STX and TTX in soft clams (Mya arenaria) and puffer fish (Tetraodon nigroviridis), respectively, offers a spectacular case of convergent evolution (Fig. 3B). For both species and toxins, a high degree of resistance is conferred by a single point mutation at the same amino acid residue (#758), located on the outer vestibule of sodium channel proteins in nerve and muscle cells (Bricelj et al., 2005; Soong and Venkatesh, 2006). An aspartic acid is substituted for a glutamic acid, causing a 1500- to 3000-fold decrease in STX/TTX binding affinity as compared to the ancestral form. Shared selection pressures and constraints acting on protein structure-function relationships promote a final, common pathway for the independent evolution of toxin resistance in distantly related species.

Interactions in the plankton. Dinoflagellates make up a significant percentage of phototrophic biomass in plankton communities and serve as important links between primary production and energy transfer throughout the trophic web (Lessard and Swift, 1985; Anderson and Sorenson, 1986; Fenchel, 1988; Mallin and Pearl, 1994). Periods of rapid cell growth facilitate increases in primary production and promote heightened energy exchange with consumers. Zooplankton grazing and nutrient limitations are key agents regulating dinoflagellate blooms (Blasco, 1977; Turner and Anderson, 1983; Uye, 1986; Berninger and Wickham, 2005) and phytoplankton composition. However, when STX and other paralytic poisons are released from cells, zooplankton feeding rates decay and monospecific blooms of chemically defended phytoplankters arise in response (Wyatt and Horwood, 1973; Fiedler, 1982; Huntley, 1982; Uye and Takamatsu, 1990).

Experimental evidence indicates that grazing pressure and the deterrent effects of STX are species-specific (Teegarden and Cembella, 1996). Whereas many zooplankton species undergo feeding suppression in harmful blooms, others are capable of consuming toxin-producing dinoflagellates. These grazers accumulate STX in their tissues and serve as vectors for toxin transfer throughout the planktonic food web (White, 1981; Boyer et al., 1985; Teegarden and Cembella, 1996; Turner et al., 2000). Consequently, STX plays a pivotal role in mediating multi-trophic interactions.

Consumption of STX-laden zooplankton or their incapacitated predators can have dramatic effects on top pelagic predators. Vertebrates such as fish (Adams et al., 1968; White, 1980, 1981), seabirds (Nisbet, 1983; Shumway et al., 2003), and marine mammals (Geraci et al., 1989; Reyero et al., 1999; Doucette et al., 2006) are much more sensitive to STX and its derivatives than are invertebrate grazers. Consequently, after dinoflagellate blooms, large-scale vertebrate mortality arises from ingestion of STX-laden planktonic organisms. Massive die-offs of top pelagic predators such as right whales (Doucette et al., 2006), monk seals (Reyero et al., 1999), and several species of fish (White, 1980, 1981) can lead to dramatic cascading effects throughout entire planktonic communities (Carpenter et al., 1985; Myers and Worm, 2003; Bruno and O'Connor, 2005).

Interactions linking plankton with benthos. A combination of STX toxicity and resistance results in profound effects at multiple trophic levels, coupling planktonic and benthic communities (Fig. 6). This phenomenon is illustrated in the Alaskan coastal ocean (Schantz et al., 1957, 1966; Quayle, 1969; Boyer et al., 1986; Kvitek and Beitler, 1991; Kvitek and Bretz, 2004). There, suspension-feeding butter clams (Saxidomus giganteus) are abundant in soft sediments, exhibit STX resistance, and sequester toxin in select tissues (Quayle, 1969; Beitler and Liston, 1990; Smolowitz and Doucette, 1995). STX and its derivatives are produced by dinoflagellates of the genus Alexandrium (previously classified as Gonyaulax or Protogonyaulax) during periodic algal blooms along the coast of southeastern Alaska (Horner et al., 1997; Van Dolah, 2000). Appropriate environmental conditions result in massive dinoflagellate blooms, and thus in elevated toxin concentrations (White, 1978; Boyer et al., 1987; Plumley, 1997; Smayda, 1997). In areas where harmful algal blooms occur seasonally (during late spring and early fall), S. giganteus retains STX at extremely high concentrations over the entire calendar year (Bricelj and Shumway, 1998). As a result, clam populations in these habitats are chemically well defended against higher order consumers.

Sea otters are major carnivores of suspension-feeding and herbivorous prey animals in both soft-sediment and kelp-forest communities of the northeastern Pacific (Kvitek et al., 1992; Estes and Duggins, 1995; Steinberg et al., 1995). Effects are especially well described for kelp forests, where otter predation considerably reduces herbivore abundance, largely releasing plants from grazing pressure. In Alaskan waters, otter predation causes significant local decline in butter clam population density and thus promotes a community dominated by alternative suspension-feeding species (Kvitek and Oliver, 1992). Historically, otters were primarily distributed offshore in areas where blooms of STX-producing dinoflagellates were infrequent (Kvitek and Oliver, 1992). Nontoxic butter clams are present at these sites and make up a majority of otter diets (Kvitek and Oliver, 1992). Recently, however, otter populations have expanded into regions of harmful blooms, where butter clams accumulate high STX concentrations. Sea otters at these overlapping sites exhibit dramatic prey switching. They avoid toxic clams and feed on other, less common marine invertebrates (Kvitek and Bretz, 2004), leading ultimately to a shift in the species composition and structure of soft-sediment communities.

Saxitoxin as a chemosensory cue

Organisms can respond behaviorally to STX (Table 2). When STX is detected, invertebrates, including several species of zooplankton grazers, reduce feeding rates or reject dinoflagellates prior to consumption (Huntley et al., 1986; Haney et al., 1995; Teegarden and Cembella, 1996). Although rejection preempts ingestion, grazers typically discard the toxic cells after physical contact, suggesting that gustatory reception is responsible for STX perception. Similarly, vertebrate predators first sample potentially dangerous prey tissues orally before switching to less toxic individuals or organs. This behavior has been observed in animals such as bivalve-siphon-nipping fish (Kvitek, 1991), sea otters (Kvitek et al., 1991; Kvitek and Bretz, 2004), and shorebirds (Goss-Custard, 1996; Bustnes, 1998; Kvitek and Bretz, 2005). Sea otters, for example, show highly specific behavioral responses to butter clams of varying STX concentrations. Prior to feeding, otters break open the bivalves and test specific tissues for STX. They readily and completely consume clams of low toxicity but discard STX-laden tissues of moderate and high toxicity (Kvitek et al., 1991; Kvitek and Bretz, 2004).

[FIGURE 6 OMITTED]

Sampling behavior in vertebrates and zooplankton indicates that taste reception mediates a conditioned aversion to STX. This hypothesis is supported by electrophysiological experiments in which gustatory receptors of anadromous fish exhibit highly sensitive and specific responses to STX (Figs. 2C and 4B; Yamamori et al., 1988). Taste receptors are differentially tuned for STX or TTX, signifying a binding mechanism different from that of voltage-gated sodium channels (Hille, 1975; Kao, 1986). Olfactory-mediated responses in Taricha newt larvae also reveal discrimination by chemosensory cells between STX and TTX (Table 1; Zimmer et al., 2006). It thus appears that the nearly identical binding interactions of STX and TTX at sodium channels differ from the highly specific interactions at gustatory and olfactory receptors. Not all receptor-binding sites are created equal.

Recapitulation and Synthesis

The guanidine alkaloids tetrodotoxin (TTX) and saxitoxin (STX) play keystone roles in natural communities. Both have multiple, opposing physiological effects with strong, but contrasting, ecological consequences. The presence of STX in phytoplankton determines the habitat and prey choices of higher order consumers, significantly impacting species compositions of coastal ocean communities (Kvitek, 1991; Kvitek and Bretz, 2004, 2005). Large, episodic die-offs of predatory fish and mammals also modify primary plant-herbivore relationships, and thus regulate trophic cascades in both benthic and pelagic environments (Carpenter et al., 1985; Myers and Worm, 2003; Bruno and O'Connor, 2005). Similarly, TTX has profound effects on trophic interactions that connect riparian stream and coastal mountain communities. Used as a chemical defense by adult newts, this compound also triggers escape reactions in conspecific larval prey and protects resistant snake species from avian raptors (Williams et al., 2004; Zimmer et al., 2006). The behavioral responses of adult and larval newts are modified further by the free amino acid arginine, in association with alternative invertebrate prey species (Ferrer and Zimmer, 2007b). Studies have demonstrated that snakes, newts, and raptors have large impacts on riparian species assemblages (Marti et al., 1993; Kurzava and Morin, 1998; Jones et al., 2001; Davic and Welsh, 2004; Smith, 2006). Our own study, for example, revealed that predation by newts depresses invertebrate prey populations (R. P. Ferrer and R. K. Zimmer, unpubl. data). Other investigations have shown that selective foraging by adult newts reverses competitive hierarchies among prey species and significantly changes community composition (Kurzava and Morin, 1998). The toxins TTX and STX thus have classic keystone characteristics. Whereas trace concentrations are typically introduced by a single species, ultimately these molecules have large impacts on many species at many trophic levels.

Concluding Remarks and Future Directions

The guanidine alkaloids are only two of several molecules potentially playing keystone roles within natural communities. In open-ocean habitats at polar latitudes, for example, dimethylsulfoniopropionate (DMSP) and its metabolites (dimethyl sulfide and acrylate) convey information among several trophic levels, including large pelagic predators, in planktonic food webs (Nevitt et al., 1995; Wolfe et al., 1997; Steinke et al., 2006; Pohnert et al., 2007). The DMSP signaling/defense pathways are vital for maintaining material exchange between primary producers, grazers, and carnivores, and have critical roles in the microbial loop (Zimmer and Butman, 2000). Alternatively, the pyrrolizidine alkaloids act as chemical defenses, mate attractants, and gustatory stimuli among many plant and resistant consumer species in terrestrial systems (Dussourd et al., 1989; Eisner and Eisner, 1991; Schulz et al., 1993; Trigo et al., 1996; Weller et al., 1999; Eisner et al., 2000; Bernays et al., 2002a, b).

Greater understanding of neuroecological phenomena will be gained through increased interdisciplinary efforts to bridge the gaps between processes that affect individuals and higher order ecological interactions. Thus far, nearly all investigations have focused at only one level of biological organization and have provided limited synthesis. Consequently, a great deal is known about parts without a clear understanding of the whole within a unified neuroecological perspective. The guanidine alkaloids tetrodotoxin (TTX) and saxitoxin (STX) are notable exceptions.

Combined studies of cell physiology and autecology (individual organisms) are especially tractable for direct experimental analysis. Hence there is an impressive body of literature on effects of chemical defense and signaling compounds (e.g., Howe, 1976; Vickers et al., 2001, Bernays et al., 2003; Kicklighter et al., 2005). Considerably less is known, however, about the community-wide impacts of such molecules.

Deciphering the roles of chemical signal/defense molecules in mediating population and community-wide processes will prove challenging. Experimental treatments would benefit from genetic manipulations to eliminate the biosynthetic capacity of primary producers, herbivores, and higher order consumers for compounds hypothesized to be keystone molecules (Baldwin et al., 2006; Izaguirre et al., 2006). Such studies could also independently involve manipulations of genes that control toxin resistance, code for the binding properties of chemosensory receptors, or both. This experimental program is a tall order indeed, and may raise concerns about using genetically engineered organisms in the field.

Alternatively, if the interactions are sufficiently strong, removing a single species may reveal a keystone effect. The elimination, for example, of Plocamium red algae high in terpenes (as chemical defenses) resulted in habitat colonization by competitively subordinate soft coral species and caused significant change in community structure (de Nys et al., 1991). Even this removal, however, did not isolate chemical defense from other potential factors mediating community-wide impacts. Similarly, experimental microcosm and mesocosm experiments in the laboratory and field have proven amenable for assigning the outcomes of chemical interactions among selected species at two or three trophic levels (Dicke et al., 2003; McIntosh et al., 2003; Linhart et al., 2005).

Coupled with these experiments, investigations could exploit biogeographical gradients in distributions of signal/defense molecules. Such gradients will provide natural laboratories for discovering the impacts of signal/defense compounds on community organization. The population density of chemically defended phytoplankton, for example, varies from high to low along a transect from inshore to offshore in Alaskan ocean waters. This natural variation has been used effectively to establish the community-wide consequences of STX (Kvitek and Bretz, 2004). Similarly, genetically distinct populations of the rough-skinned newt are found among equivalent habitats in northern California, Oregon, Washington, and southern British Columbia. The populations differ considerably in TTX concentration, from none to highly toxic levels (Hanifin et al., 1999; Brodie et al., 2002). Through careful selection of populations and habitats, it may be possible to identify community-wide properties that vary uniquely as a function of TTX concentration.

By using these natural laboratories, it will be possible to establish broad community-wide patterns that motivate controlled experiments, in field or laboratory, on targeted individual or species interactions. Thus, integrating a wide repertoire of quantitative, natural historical, and experimental approaches would establish a composite neuroecological picture from its physiological, behavioral, and ecological parts. The resulting knowledge will define the effects of chemical signal/defense molecules on cellular processes and determine their consequences within natural communities. It also will determine the extent to which the keystone concept can be applied as a basic neuroecological principle. Finally, it will establish where impacts attributed to keystone species arise not from biological interactions, but as a consequence of chemistry.

Acknowledgments

We thank C.A. Zimmer and members of the UCLA graduate seminar in Chemical Ecology (A. E. Nichols, G. A. Ferrier, A. J. Corcoran, and S. B. Olssen) for their assistance in developing ideas linking chemical defenses, chemical signals, and the keystone species hypothesis. C. D. Derby was an early and gracious collaborator in hatching the neuroecology concept. His invitation for a seminar, as well as strong encouragement, led to organizing these thoughts into a collective body of work. Comments by J. B. McClintock and an anonymous reviewer greatly improved an earlier draft of the manuscript. This research was supported by awards from the National Science Foundation (OCE 02-42321) and California Sea Grant (Project # R/F-147).

Literature Cited

Adams, J. A., D. D. Seaton, J. B. Buchanan, and M. R. Longbottom. 1968. Biological observations associated with the toxic phytoplankton bloom off the east coast. Nature 220: 24-25.

Anderson, P., and H. M. Sorenson. 1986. Population dynamics and trophic coupling in pelagic microorganisms in eutrophic coastal waters. Mar. Ecol. Prog. Ser. 33: 99-109.

Arnold, T. M., and N. M. Targett. 2002. Marine tannins: the importance of a mechanistic framework for predicting ecological roles. J. Chem. Ecol. 28: 1919-1934.

Backx, P., D. Yue, J. Lawrence, E. Marban, and G. Tomaselli. 1992. Molecular localization of an ion-binding site within the pore of mammalian sodium channels. Science 257: 248-251.

Baker, T. R., G. J. Doucette, C. L. Powell, G. L. Boyer, and F. G. Plumley. 2003. [GTX.sub.4] imposters: characterization of fluorescent compounds synthesized by Pseudomonas stutzeri SF/PS and Pseudomonas/Alteromonas PTB-1, symbionts of saxitoxin-producing Alexandrium spp. Toxicon 41: 339-347.

Baldwin, I. T., R. Halitschke, A. Paschold, C. C. von Dahl, and C. A. Preston. 2006. Volatile signaling in plant-plant interactions: "talking trees" in the genomics era. Science 311: 812-815.

Bates, H. A., R. Rostriken, and H. Rapaport. 1978. The occurrence of saxitoxin and other toxins in various dinoflagellates. Toxicon 16: 595-602.

Beitler, M. K., and J. Listen. 1990. Uptake and tissue distribution of PSP toxins in butter clams. Pp. 257-262 in Toxic Marine Phytoplankton, J. R. Graneli, E. B. Sunstrom, L. Edler, and D. M. Anderson, eds. Elsevier, New York.

Bernays, E. A., R. F. Chapman, and T. Hartmann. 2002a. A highly sensitive taste receptor cell for pyrrolizidine alkaloids in the lateral galeal sensillum of a polyphagous caterpillar, Estigmene acrea. J. Comp. Physiol. A 188: 715-723.

Bernays, E. A., R. F. Chapman, and T. Hartmann. 2002b. A taste receptor neurone dedicated to the perception of pyrrolizidine alkaloids in the medial galeal sensillum of two polyphagous arctiid caterpillars. Physiol. Entomol. 27: 312-321.

Bernays, E. A., D. Rodrigues, R. F. Chapman, M. S. Singer, and T. Hartmann. 2003. Loss of gustatory responses to pyrrolizidine alkaloids after their extensive ingestion in the polyphagous caterpillar Estigmene acrea. J. Exp. Biol. 206: 4487-4496.

Berninger, U. G., and S. A. Wickham. 2005. Response of the microbial food web manipulations of nutrients and grazers in the oligotrophic Gulf of Aqaba and northern Red Sea. Mar. Biol. 147: 1017-1032.

Blackburn, N., T. Fenchel, and J. Mitchell. 1998. Microscale nutrient patches in planktonic habitats shown by chemotactic bacteria. Science 282: 2254-2256.

Blasco, D. 1977. Red tide in the upwelling region of Baja California. Limnol. Oceanogr. 22: 255-263.

Boyer, G. L., J. J. Sullivan, M. LeBlanc, and R. J. Anderson. 1985. The assimilation of PSP toxins by the copepod Tigriopus californicus from dietary Protogonyaulax catenella. Pp. 407-412 in Toxic Dinoflagellates, D. M. Anderson, A. W. White, and D. G. Baden, eds. Elsevier, New York.

Boyer, G. L., J. J. Sullivan, R. J. Anderson, F. J. R. Taylor, P. J. Harison, and A. D. Cembella. 1986. Use of high-performance liquid chromatography to investigate the production of paralytic shellfish toxins by Protogonyaulax spp. in culture. Mar. Biol. 93: 361-369.

Boyer, G. L., J. J. Sullivan, R. J. Anderson, P. J. Harrison, and F. J. R. Taylor. 1987. Effects of nutrient limitation on toxin production and composition in the marine dinoflagellate Protogonyaulax tamarensis. Mar. Biol. 96: 123-128.

Bray, S., and H. Amrein. 2003. A putative Drosophila pheromone receptor expressed in male-specific taste neurons is required for efficient courtship. Neuron 39: 1019-1029.

Bricelj, V. M., and S. E. Shumway. 1998. Paralytic shellfish toxins in bivalve mollusks: occurrence, transfer kinetics, and biotransformation. Rev. Fish Sci. 6: 315-383.

Bricelj, V. M., J. H. Lee, A. D. Cembella, and D. M. Anderson. 1990. Uptake of Alexandrium fundyense by Mytilus edulis and Mercenaria mercenaria under controlled conditions. Pp. 269-274 in Toxic Marine Phytoplankton, E. Graneli, B. Sundstom, L. Edler, and D. M. Anderson, eds. Academic Press, New York.

Bricelj, V. M., L. Connell, K. Konoki, S. P. MacQuarrie, T. Sheuer, W. A. Catterall, and V. L. Trainer. 2005. Sodium channel mutation leading to saxitoxin resistance in clams increases risk of PSP. Nature 434: 763-767.

Brodie, E. D., Jr. 1968. Investigations on the skin toxin of the adult rough-skinned newt, Taricha granulosa. Copeia 1968: 307-313.

Brodie, E. D., Jr., B. J. Ridenhour, and E. D. Brodie III. 2002. The evolutionary response of predators to dangerous prey: hotspots and coldspots in the geographic mosaic of coevolution between garter snakes and newts. Evolution 56: 2067-2082.

Brodie, E. D., III., and E. D. Brodie, Jr. 1990. Tetrodotoxin resistance in garter snakes: an evolutionary response of predators to dangerous prey. Evolution 44: 651-659.

Brodie, E. D., III, and E. D. Brodie, Jr. 1999. Predator-prey arms races: asymmetrical selection on predators and prey may be reduced when prey are dangerous. Bioscience 49: 557-568.

Brodie, E. D., III, C. R. Feldman, C. T. Hanifin, J. E. Motychak, D. G. Mulcahy, B. L. Williams, and E. D. Brodie, Jr. 2005. Parallel arms races between garter snakes and newts involving tetrodotoxin as the phenotypic interface of coevolution. J. Chem. Ecol. 31: 343-356.

Bruno, J. F., and M. I. O'Connor. 2005. Cascading effects of predatory diversity and omnivory in a marine food web. Ecol. Lett. 8: 1048-1056.

Buchwald, H. D., L. Durham, H. G. Fisher, R. Harada, H. S. Mosher, C. Y. Kao, and F. A. Fuhrman. 1964. Identity of tarichatoxin and tetrodotoxin. Science 143: 474-475.

Bustnes, J. O. 1998. Selection of blue mussels, Mytilus edulis, by common eiders, Somateria mollissima, by size in relation to shell content. Can. J. Zool. 76: 1787-1790.

Camacho, F. A., and R. W. Thacker. 2006. Amphipod herbivory on the freshwater cyanobacterium Lyngbya wollei: chemical stimulants and morphological defenses. Limnol. Oceanogr. 51: 1870-1875.

Carpenter, S. R., J. F. Kitchell, and J. R. Hodgson. 1985. Cascading trophic interactions and lake productivity. Bioscience 35: 634-639.

Catterall, W. A. 1988. Structure and function of voltage-sensitive ion channels. Science 242: 50-61.

Catterall, W. A. 1992. Cellular and molecular biology of voltage-dependent sodium channels. Physiol. Rev. 72: S15-S48.

Cestele, S., and W. A. Catterall. 2000. Molecular mechanisms of neurotoxin action on voltage-gated sodium channels. Biochimie 82: 883-892.

Chen, L.Q., M. Chahine, R. G. Kallen, R. L. Barchi, and R. Horn. 1992. Chimeric study of sodium channels from rat skeletal and cardiac muscle. FEBS Lett. 309: 253-257.

Choudhary, G., M. Yotsu-Yamashita, L. Shang, T. Yasumoto, and S. C. Dudley, Jr. 2003. Interactions of the C-11 hydroxyl of tetrodotoxin with the sodium channel outer vestibule. Biophys. J. 84: 287-294.

Cruz-Rivera, E., and T. A. Villareal. 2006. Macroalgal palatability and the flux of ciguatera toxins through marine food webs. Harmful Algae 5: 497-525.

Daly, J. W. 1995. The chemistry of poisons in amphibian skin. Proc. Natl. Acad. Sci. USA 92: 9-13.

Davic, R. D., and H. H. Welsh. 2004. On the ecological roles of salamanders. Annu. Rev. Ecol. Evol. Syst. 35: 405-434.

de Nys, R., J. C. Coll, and I. R. Price. 1991. Chemically mediated interactions between the red alga Plocamium hamatum (Rhodophyta) and the octocoral Sinularia cruciata (Alcyonacea). Mar. Biol. 108: 315-320.

Dicke, M., J. G. de Boer, M. Hofte, and C. M. Rocha-Granados. 2003. Mixed blends of herbivore-induced plant volatiles and foraging success of carnivorous arthropods. Oikos 101: 38-48.

Doucette, G. J., A. D. Cembella, J. L. Martin, J. Michaud, T. V. N. Cole, and R. M. Rolland. 2006. Paralytic shellfish poisoning (PSP) toxins in North Atlantic right whales Eubalaena glacialis and their zooplankton prey in the Bay of Fundy, Canada. Mar. Ecol. Prog. Ser. 306: 303-313.

Dreanno, C., K. Matsumura, N. Dohmae, K. Takio, H. Hirota, R. B. Kirby, and A. S. Clare. 2006. An [alpha]-macroglobulin-like protein is the cue to gregarious settlement of the barnacle Balanus amphitrite. Proc. Natl. Acad. Sci. USA 103: 14396-14401.

Duggins, D. O., C. A. Simenstad, and J. A. Estes. 1989. Magnification of secondary production by kelp detritus in coastal marine ecosystems. Science 245: 170-173.

Dussourd, D. E., C. A. Harvis, J. Meinwald, and T. Eisner. 1991. Pheromonal advertisement of a nuptial gift by a male moth (Utethesia ornatrix). Proc. Natl. Acad. Sci. USA 88: 9224-9227.

Eisner, T., and M. Eisner. 1991. Unpalatability of the pyrrolizidine alkaloid-containing moth Utetheisa ornatrix and its larva to wolf spiders. Psyche 98: 111-118.

Eisner, T., M. Eisner, C. Rossini, V. K. Iyengar, B. L. Roach, E. Benedikt, and J. Meinwald. 2000. Chemical defense against predation in an insect egg. Proc. Natl. Acad. Sci. USA 97: 1634-1639.

Elliot, S. A., L. B. Kats, and J. A. Breeding. 1993. The use of conspecific chemical cues for cannibal avoidance in California newts (Taricha torosa). Ethology 95: 186-192.

Emelyhanova, L. V., E. M. Koroleva, and M. V. Savina. 2004. Glucose and free amino acids in the blood of lampreys (Lampetra fluviatilis L.) and frogs (Rana temporaria L.) under prolonged starvation. Comp. Biochem. Physiol. 138A: 527-532.

Estes, J. A., and D. O. Duggins. 1995. Sea otters and kelp forests in Alaska: generality and variation in a community ecological paradigm. Ecol. Monogr. 65: 75-100.

Estes, J. A., and J. F. Palmisano. 1974. Sea otters: their role in structuring nearshore communities. Science 185: 1058-1060.

Evans, M. H. 1972. Tetrodotoxin, saxitoxin, and related substances: their application in neurobiology. Int. Rev. Neurobiol. 15: 83-166.

Fenchel, T. 1988. Marine plankton food chains. Annu. Rev. Ecol. Syst. 19: 19-38.

Ferrer, R. P., and R. K. Zimmer. 2007a. Chemosensory reception, behavioral expression, and ecological interactions at multiple trophic levels. J. Exp. Biol. 210: 1776-1785.

Ferrer, R. P., and R. K. Zimmer. 2007b. The scent of danger: arginine as an olfactory cue of reduced predation risk. J. Exp. Biol. 210: 1768-1775.

Fiedler, P. 1982. Zooplankton avoidance and reduced grazing responses to Gymnodinium splendens (Dinophyceae). Limnol. Oceanogr. 27: 961-965.

Gallacher, S., K. J. Flynn, J. M. Franco, E. E. Brueggemann, and H. B. Hines. 1997. Evidence for production of paralytic shellfish toxins by bacteria associated with Alexandrium spp. (Dinophyta) in culture. Appl. Environ. Microbiol. 63: 239-245.

Gallardo, M. A., M. I. Ferrer, and J. Sanchez. 1994. Presence of an [X.sub.AG] carrier in frog (Rana exculenta) red blood cells. J. Membr. Biol. 139: 97-102.

Gamradt, S. C., and L. B. Kats. 1996. Effects of introduced crayfish and mosquitofish on California newts. Conserv. Biol. 10: 1155-1162.

Geffeney, S., E. D. Brodie, Jr., P. C. Ruben, and E. D. Brodie III. 2002. Mechanisms of adaptation in a predator-prey arms race: TTX-resistant sodium channels. Science 297: 1336-1339.

Geffeney, S. L., E. Fujimoto, E. D. Brodie III, E. D. Brodie, Jr., and P. C. Ruben. 2005. Evolutionary diversification of TTX-resistant sodium channels in a predator-prey interaction. Nature 434: 759-763.

Geraci, J. R., D. M. Anderson, R. J. Timperi, D. J. St. Aubin, G. A. Early, J. H. Prescott, and C. A. Mayo. 1989. Humpback whales (Megaptera novaeangliae) fatally poisoned by dinoflagellate toxin. Can. J. Fish. Aquat. Sci. 46: 1895-1898.

Goss-Custard, J. D. 1996. The Oystercatcher: from Individuals to Populations. Oxford University Press, New York.

Gosselin, S., L. Fortier, and J. A. Gagne. 1989. Vulnerability of marine fish larvae to the toxic dinoflagellate Protogonyaulax tamarensis. Mar. Ecol. Prog. Ser. 57: 1-10.

Haney, J. F., J. J. Sasner, and M. Ikawa. 1995. Effects of products released by Aphanizomenon flos aquae and purified saxitoxin on the movements of Daphnia carinata feeding appendages. Limnol. Oceanogr. 40: 263-272.

Hanifin, C. T., M. Yotsu-Yamashita, T. Yasumoto, E. D. Brodie III, and E. D. Brodie, Jr. 1999. Toxicity of dangerous prey: variation of tetrodotoxin levels within and among populations of the newt Taricha granulosa. J. Chem. Ecol. 25: 2161-2175.

Hanifin, C. T., E. D. Brodie III, and E. D. Brodie, Jr. 2002. Tetrodotoxin levels of the rough-skin newt, Taricha granulosa, increase in long-term captivity. Toxicon 40: 1149-1153.

Hanifin, C. T., E. D. Brodie III, and E. D. Brodie, Jr. 2003. Tetrodotoxin levels in eggs of the rough-skin newt, Taricha granulosa, are correlated with female toxicity. J. Chem. Ecol. 29: 1729-1739.

Hansen, P. J. 1989. The red tide dinoflagellate Alexandrium tamarense: effects on behaviour of and growth of a tintinnid ciliate. Mar. Ecol. Prog. Ser. 53: 105-116.

Hansen, P. J., A. D. Cembella, and O. Moestrup. 1992. The marine dinoflagellate Alexandrium ostenfeldii: paralytic shellfish toxin concentration, composition, and toxicity to a tintinnid ciliate. J. Phycol. 28: 597-603.

Hansen-Bay, C. M., and G. R. Strichartz. 1980. Saxitoxin binding to sodium channels of rat skeletal muscles. J. Physiol. 300: 89-103.

Hanson, K., J. Snyder, and L. B. Kats. 1994. Taricha torosa (Diet). Herpetol. Rev. 25: 62.

Hay, M. E., and W. Fenical. 1988. Marine plant-herbivore interactions: the ecology of chemical defense. Annu. Rev. Ecol. Syst. 19: 111-145.

Heinemann, S. H., H. Terlau, W. Stiihmer, K. Imoto, and S. Numa. 1992. Calcium channel characteristics conferred on the sodium channel by single mutations. Nature 356: 441-443.

Helfield, J. M., and R. J. Naiman. 2006. Keystone interactions: salmon and bears in riparian forests of Alaska. Ecosystems 9: 167-180.

Herms, D. A., and W. J. Mattson. 1992. The dilemma of plants to grow or defend. Q. Rev. Biol. 67: 283-335.

Hilderbrand, G. V., T. A. Hanley, C. T. Robbins, and C. C. Schwartz. 1999. Role of brown bears (Ursus arctos) in the flow of marine nitrogen into a terrestrial ecosystem. Oecologia 121: 546-550.

Hille, B. 1975. The receptor for tetrodotoxin and saxitoxin. Biophys. J. 15: 615-619.

Hille, B. 1984. Ionic Channels of Excitable Membranes. Sinauer, Sunderland, MA.

Horner, R. A., D. L. Garrison, and F. G. Plumley. 1997. Harmful algal blooms and red tide problems on the U.S. west coast. Limnol. Oceanogr. 42: 1076-1088.

Howe, N. R. 1976. Behavior of sea anemones evoked by the alarm pheromone anthopleurine. J. Comp. Physiol. A 107: 67-76.

Huntley, M. 1982. Yellow water in La Jolla Bay, California, July 1980. II. Suppression of zooplankton grazing. J. Exp. Mar. Biol. Ecol. 63: 81-91.

Huntley, M., P. Sykes, S. Rohan, and V. Marin. 1986. Chemically-mediated rejection of dinoflagellate prey by the copepods Calanus pacificus and Paracalanus parvus: mechanism, occurrence and significance. Mar. Ecol. Prog. Ser. 28: 105-120.

Hwang, P., T. Noguchi, and D. Hwang. 2004. Neurotoxin tetrodotoxin as attractant for toxic snails. Fish. Sci. 70: 1106-1112.

Ives, J. D. 1985. The relationship between Gonyaulax tamarensis cell toxin levels and copepod ingestion rates. Pp. 413-418 in Toxic Dinoflagellates, D. M. Anderson, A. W. White, and D. G. Baden, eds. Elsevier, New York.

Ives, J. D. 1987. Possible mechanisms underlying copepod grazing responses to levels of toxicity in red tide dinoflagellates. J. Exp. Mar. Biol. Ecol. 112: 131-145.

Izaguirre, M. M., C. A. Mazza, M. Biondini, I. T. Baldwin, and C. L. Ballare. 2006. Remote sensing of future competitors: impacts on plant defenses. Proc. Natl. Acad. Sci. USA 103: 7170-7174.

Jackim, E., and J. Gentile. 1968. Toxins of a blue-green alga: similarity to saxitoxin. Science 162: 915-916.

Janzen, D. H. 1977. Why fruits rot, seeds mold, and meat spoils. Am. Nat. 111: 691-713.

Jennings, M. R., and M. P. Hayes. 1994. Amphibian and reptile species of special concern in California. California Department of Fish and Game, Inland Fisheries Division, Rancho Cordova, CA.

Johnston, R. E. 2003. Chemical communication in rodents: from pheromones to individual recognition. J. Mammal. 84: 1141-1162.

Jonas-Davies, J., and J. Liston. 1985. The occurrence of PSP toxins in intertidal organisms. Pp. 467-472 in Toxic Dinoflagellates, D. M. Anderson, A. W. White, and D. G. Baden, eds. Elsevier, New York.

Jones, C. G., J. H. Lawton, and M. Shachak. 1994. Organisms as ecosystem engineers. Oikos 69: 373-386.

Jones, C. G., J. H. Lawton, and M. Shachak. 1997. Positive and negative effects of organisms as physical ecosystem engineers. Ecology 78: 1946-1957.

Jones, M., Y. Mandelik, and T. Dayan. 2001. Coexistence of temporally partitioned spiny mice: roles of habitat structure and foraging behavior. Ecology 82: 2164-2176.

Kaneko, Y., G. Matsumoto, and Y. Hanyu. 1997. TTX resistivity of [Na.sup.+] channel in newt retinal neuron. Biochem. Biophys. Res. Commun. 240: 651-656.

Kao, C. Y. 1966. Tetrodotoxin, saxitoxin and their significance in the study of excitation phenomena. Pharmacol. Rev. 18: 997-1049.

Kao, C. Y. 1986. Structure-activity relations of tetrodotoxin, saxitoxin and analogues. Ann, NY Acad. Sci. 479: 52-67.

Kao, C. Y., and F. A. Fuhrman. 1963. Pharmalogical studies on tarichatoxin, a potent neurotoxin. J. Pharm. Exp. Ther. 140: 31-40.

Kao, C. Y., and S. E. Walker. 1982. Active groups of saxitoxin and tetrodotoxin as deduced from action of saxitoxin analogues on frog muscle and squid axon. J. Physiol. 323: 619-637.

Kats, L. B., S. A. Elliot, and J. Currens. 1992. Intraspecific oophagy in stream-breeding California newts (Taricha torosa). Herpetol. Rev. 23: 7-8.

Keeling, C. I., K. N. Slessor, H. A. Higo, and M. L. Winston. 2003. New components of the honey bee (Apis mellifera L.) queen retinue pheromone. Proc. Natl. Acad. Sci. USA 100: 4486-4491.

Kerby, J. L., and L. B. Kats. 1998. Modified interactions between salamander life stages caused by wildfire-induced sedimentation. Ecology 79: 740-745.

Kicklighter, C. E., S. Shabani, P. M. Johnson, and C. D. Derby. 2005. Sea hares use novel antipredatory chemical defenses. Curr. Biol. 15: 549-554.

Kim, Y. H., G. B. Brown, H. S. Moher, and F. A. Fuhrman. 1975. Tetrodotoxin: occurrence in atelopid frogs of Costa Rica. Science 189: 151-152.

Kodama, M., T. Ogata, and S. Sato. 1988. Bacteria production of saxitoxin. Agric. Biol. Chem. 52: 1075-1077.

Kodama, M., T. Ogata, S. Sakamoto, S. Sato, T. Honda, and T. Miwatani. 1990. Production of paralytic shellfish toxins by a bacterium Moraxella sp. isolated from Protogonyaulax tamarensis. Toxicon 28: 707-714.

Kogure, K., H. K. Do, D. Kim, and Y. Shirayama. 1996. High concentration of neurotoxin in free-living marine nematodes. Mar. Ecol. Prog. Ser. 136: 147-151.

Kontis, K. J., and A. L. Goldin. 1993. Site-directed mutagenesis of the putative pore region of the rat IIA sodium channel. Mol. Pharmacol. 43: 635-644.

Kotaki, Y., and Y. Shimizu. 1993. 1-Hydroxy-5, 11-dideoxytetrodotoxin, the first N-hydroxy and ring-deoxy derivative of tetrodotoxin found in the newt Taricha granulosa. J. Am. Chem. Soc. 115: 827-830.

Kurzava, L. M., and P. J. Morin. 1998. Tests of functional equivalence: complementary roles of salamanders and fish in community organization. Ecology 79: 477-489.

Kvitek, R. G. 1991. Paralytic shellfish toxins sequestered by bivalves as a defense against siphon-nipping fish. Mar. Biol. 111: 369-374.

Kvitek, R. G., and M. K. Beitler 1991. Relative insensitivity of butter clam neurons to saxitoxin: a pre-adaptation for sequestering paralytic shellfish poisoning toxins as a chemical defense. Mar. Ecol. Prog. Ser. 69: 47-54.

Kvitek, R. G., and C. Bretz. 2004. Harmful algal bloom toxins protect bivalve populations from sea otter predation. Mar. Ecol. Prog. Ser. 271: 233-234.

Kvitek, R. G., and C. Bretz. 2005. Shorebird foraging behavior, diet, and abundance vary with harmful algal bloom toxin concentrations in invertebrate prey. Mar. Ecol. Prog. Ser. 293: 303-309.

Kvitek, R. G., and J. S. Oliver. 1992. The influence of sea otters on prey communities in southeast Alaska. Mar. Ecol. Prog. Ser. 82: 103-113.

Kvitek, R. G., A. R. DeGange, and M. K. Beitler. 1991. Paralytic shellfish poisoning toxins mediate feeding behavior of sea otters. Limnol. Oceanogr. 36: 393-404.

Kvitek, R. G., J. S. Oliver, A. R. DeGange, and B. S. Anderson. 1992. Changes in soft-bottom prey communities along a gradient in sea otter predation. Ecology 73: 413-428.

Last, J. M. 1980. The food of twenty species of fish larvae in the west-central North Sea. Fisheries Research Technical Report 60, Ministry of Agriculture, Fisheries and Food, Lowestoft, United Kingdom.

Lecchini, D., J. Shima, B. Banaigs, and R. Galzin. 2005. Larval sensory abilities and mechanisms of habitat selection of a coral reef fish during settlement. Oecologia 143: 326-334.

Lessard, E. J., and E. Swift. 1985. Species specific grazing rates of heterotrophic dinoflagellates in oceanic waters measured with a dual label radioisotope technique. Mar. Biol. 87: 289-296.

Li, K. M. 1963. Action of puffer fish poison. Nature 200: 791.

Lindquist, N., and M. E. Hay. 1996. Palatability and chemical defense of marine invertebrate larvae. Ecol. Monogr. 66: 431-450.

Linhart, Y. B., K. Keefover-Ring, K. A. Mooney, B. Breland, and J. D. Thompson. 2005. A chemical polymorphism in a multitrophic setting: thyme monoterpene composition and food web structure. Am. Nat. 166: 517-529.

Lipkind, G. M., and H. A. Fozzard. 1994. A structural model of the tetrodotoxin and saxitoxin binding site of the [Na.sup.+] channel. Biophys. J. 66: 1-13.

Llewellyn, L. A. 1997. Haemolymph protein in xanthid crabs: its selective binding of saxitoxin and possible role in toxin bioaccumulation. Mar. Biol. 128: 599-606.

Llewellyn, L., A. Negri, and A. Robertson. 2006. Paralytic shellfish toxins in tropical oceans. Toxin Rev. 25: 159-196.

Mallin, M. A., and H. W. Pearl. 1994. Planktonic trophic transfer in an estuary: seasonal, diel, and community structure effects. Ecology 75: 2168-2184.

Marsden, I. D., and S. E. Shumway. 1995. The effect of a toxic dinoflagellate (Alexandrium tamarense) on the oxygen uptake of juvenile filter-feeding bivalve mollusks. Comp. Biochem. Physiol. 106A: 769-773.

Marti, C. D., K. Steenhof, M. N. Kochert, and J. S. Marks. 1993. Community trophic structure: the roles of diet, body size, and activity time in vertebrate predators. Oikos 67: 6-18.

Matsumura, K. 1995. Tetrodotoxin as a pheromone. Nature 378: 563-564.

McAllister, K. R., J. Seriletz, B. Hall, and M. M. Garner. 1997. Taricha granulosa (roughskin newt) toxicity. Herpetol. Rev. 28: 82.

McClintock, J. B., and B. J. Baker. 1997. A review of the chemical ecology of Antarctic marine invertebrates. Am. Zool. 37: 329-342.

McIntosh, A. R., B. L. Peckarsky, and B. W. Taylor. 2003. Predator-induced resource heterogeneity in a stream food web. Ecology 85: 2279-2290.

McKey, D. 1974. Adaptive patterns in alkaloid physiology. Am. Nat. 108: 305-320.

Menge, B. A., C. Blanchette, P. Raimondi, T. Feidenburg, S. Gaines, J. Lubchenco, D. Lohse, G. Hudson, M. Foley, and J. Pamplin. 2004. Species interaction strength: testing model predictions along an up-welling gradient. Ecol. Monogr. 74: 663-684.

Miyazawa, K., J. K. Jeon, J. Maruyama, T. Noguchi, K. Ito, and K. Hashimoto. 1986. Occurrence of tetrodotoxin in the flatworm Planocera multitentaculata. Toxicon 24: 645-650.

Mobley, J. A., and T. A. Stidham. 2000. Great horned owl death from predation of a toxic California newt. Wilson Bull. 112: 563-564.

Myers, R. A., and B. Worm. 2003. Rapid depletion of predatory fish communities. Nature 423: 280-283.

Nagai, K., Y. Matsuyama, T. Uchida, S. Akamatsu, and T. Honjo. 2000. Effect of a natural population of the harmful dinoflagellate Heterocapsa circularisquama on the survival of the pearl oyster Pinctada fucata. Fish. Sci. 66: 995-997.

Nagle, D. G., and V. J. Paul. 1998. Chemical defense of a marine cyanobacterial bloom. J. Exp. Mar. Biol. Ecol. 225: 29-38.

Nakamura, M., Y. Oshima, and T. Yasumoto. 1984. Occurrence of saxitoxin in puffer fish. Toxicon 22: 381-385.

Negri, A. P., and G. J. Jones. 1995. Bioaccumulation of paralytic shellfish poisoning (PSP) toxins from the cyanobacterium Anabaena circinalis by the freshwater mussel Alathyria condola. Toxicon 33: 667-678.

Nevitt, G. A., R. R. Veit, and P. Kareiva. 1995. Dimethyl sulfide as a foraging cue for Antarctic procellariiform seabirds. Nature 376: 680-682.

Nisbet, I. C. 1983. Paralytic shellfish poisoning: effects on breeding terns. Condor 85: 338-345.

Noda, M., H. Suzuki, S. Numa, and W. Stuhmer. 1989. A single point mutation confers tetrodotoxin and saxitoxin insensitivity on the sodium channel II. FEBS Lett. 259: 213-216.

Noguchi, T., J. K. Jeon, O. Arakawa, H. Sugita, Y. Deguchi, Y. Shida, and K. Hashimoto. 1986. Occurrence of tetrodotoxin and anhydrotetrodotoxin in Vibrio sp. isolated from the intestine of a xanthid crab Atergatis fluorides. J. Biochem. 99: 311-314.

Paine, R. T. 1966. Food web complexity and species diversity. Am. Nat. 100: 65-75.

Painter, S. D., B. Clough, R. W. Garden, J. V. Sweedler, and G. T. Nagle. 1998. Characterization of Aplysia attractin, the first waterborne peptide pheromone in invertebrates. Biol. Bull. 194: 120-131.

Pawlik, J. R. 1993. Marine invertebrate chemical defenses. Chem. Rev. 93: 1911-1922.

Penzotti, J. L., H. A. Fozzard, G. M. Lipkind, and S. C. Dudley, Jr. 1998. Differences in saxitoxin and tetrodotoxin binding revealed by mutagenesis of the [Na.sup.+] channel outer vestibule. Biophys. J. 75: 2647-2657.

Pimentel, R. A. 1952. Studies on the biology of Triturus granulosus Skilton. Ph.D. dissertation, Oregon State University, Corvalis, OR.

Pin, J. P., T. Galvez, and L. Prezeau. 2003. Evolution, structure, and activation mechanism of family 3/C G-protein-coupled receptors. Pharmacol. Ther. 98: 325-354.

Plumley, F. G. 1997. Marine algal toxins: biochemistry, genetics, and molecular biology. Limnol. Oceanogr. 42: 1252-1264.

Pohnert, G., M. Steinke, and R. Tollrian. 2007. Chemical cues, defence metabolites and the shaping of pelagic interspecific interactions. Trends Ecol. Evol. 22: 198-204.

Power, M. E., D. Tilman, J. Estes, B. A. Menge, W. J. Bond, L. S. Mills, G. Daily, J. C. Castilla, J. Lubchenko, and R. T. Paine. 1996. Challenges in the quest for keystones. Bioscience 46: 609-620.

Proctor, N. H., S. L. Chan, and A. J. Trevor. 1975. Production of saxitoxin by cultures of Gonyaulax catenella. Toxicon 13: 1-9.

Quayle, D. B. 1969. Paralytic shellfish poisoning in British Columbia. Bull. Fish. Res. Board Can. 168: 1-69.

Reyero, M., E. Cacho, A. Martinez, J. Vasquez, A. Marina, S. Fraga, and J. M. Franco. 1999. Evidence of saxitoxin derivatives as causative agents in the 1997 mass mortality of monk seals in the Cape Blanc Peninsula. Nat. Toxins 7: 311-315.

Rhodes, D. F., and R. G. Cates. 1976. Toward a general theory of plant antiherbivore chemistry. Recent Adv. Phytochem. 10: 168-213.

Riffell, J. A., P. J. Krug, and R. K. Zimmer. 2004. The ecological and evolutionary consequences of sperm chemoattraction. Proc. Natl. Acad. Sci. USA 101: 4501-4506.

Riley, S. P. D., G. T. Busteed, L. B. Kats, T. L. Vandergon, L. F. S. Lee, R. G. Dagit, J. L. Kerby, R. N. Fisher, and R. M. Sauvigot. 2005. Effects of urbanization on the distribution and abundance of amphibians and invasive species in southern California streams. Conserv. Biol. 19: 1894-1907.

Ritchie, K. B., I. Nagelkerken, S. James, and G. W. Smith. 2000. A tetrodotoxin-producing marine pathogen. Nature 404: 354.

Ritson-Williams, R., M. Yotsu-Yamashita, and V. J. Paul. 2006. Ecological functions of tetrodotoxin in a deadly polyclad flatworm. Proc. Natl. Acad. Sci. USA 103: 3176-3179.

Robineau, B., J. A. Gagne, L. Fortier, and A. D. Cembella. 1991. Potential impact of a toxic dinoflagellate (Alexandrium excavatum) bloom on survival of fish and crustacean larvae. Mar. Biol. 108: 293-301.

Ruel, J. J., and M. P. Ayers. 1999. Jensen's inequality predicts effects of environmental variation. Trends Ecol. Evol. 14: 361-366.

Satin, J., J. W. Kyle, M. Chen, P. Bell, L. L. Cribbs, H. A. Fozzard, and R. B. Rogart. 1992. A mutant of TTX-resistant cardiac sodium channels with TTX-sensitive properties. Science 256: 1202-1205.

Schantz, E. J. 1986. Chemistry and biology of saxitoxin and related toxins. Ann. NY Acad. Sci. 479: 15-23.

Schantz, F. J., J. D. Mold, D. W. Sanger, J. Shavel, F. J. Riel, J. P. Bowden, J. M. Lynch, R. S. Wyler, B. Reigel, and H. Sommer. 1957. Paralytic shellfish poison. VI. A procedure for the isolation and purification of the poison from toxic clams and mussel tissues. J. Am. Chem. Soc. 78: 5230-5233.

Schantz, F. J., J. M. Lynch, G. Vayvada, K. Matsumoto, and H. Rapoport. 1966. The purification and characterization of the poison produced by Gonyaulax catenella in axenic culture. Biochemistry 5: 1191-1195.

Schulz, S., W. Francke, M. Boppre, T. Eisner, and J. Meinwald. 1993. Defense mechanisms of arthropods: stereochemical pathway of hydroxydanaidal production from alkaloid precursors in Creatonotos transiens (Lepidoptera, Arctiidae). Proc. Natl. Acad. Sci. USA 90: 6834-6838.

Sherman, S. J., J. C. Lawrance, D. J. Messner, K. Jacoby, and W. A. Catterall. 1983. Tetrodotoxin-sensitive sodium channels in rat muscle cells developing in vitro. J. Biol. Chem. 258: 2488-2495.

Sheumack, D. D., M. E. H. Howden, L. Spense, and R. J. Quinn. 1978. Maculotoxin: a neurotoxin from the venom glands of the octopus Hapalochlaena maculosa identified as tetrodotoxin. Science 199: 188-189.

Shimizu, Y. 1987. Dinoflagellate toxins. Pp. 282-315 in The Biology of Dinoflagellates, F. J. R. Taylor, ed. Blackwell Scientific, Oxford.

Shumway, S. E., S. M. Allen, and P. D. Boersma. 2003. Marine birds and harmful algal blooms: sporadic victims or under-reported events? Harmful Algae 2: 1-17.

Smayda, T. 1997. What is a bloom? A commentary. Limnol. Oceanogr. 42: 1132-1136.

Smith, K. G. 2006. Keystone predators (eastern newts, Notophthalmus viridescens) reduce the impacts of an aquatic invasive species. Oecologia 148: 342-349.

Smolowitz, R., and G. Doucette. 1995. Immunohistochemical localization of saxitoxin in the siphon epithelium of the butter clam, Saxidomus giganteus. Biol. Bull. 189: 229-230.

Soong, T. W., and B. Venkatesh. 2006. Adaptive evolution of tetrodotoxin resistance in animals. Trends Genet. 22: 621-626.

Stebbins, R. C. 1972. Amphibians and Reptiles of California. University of California Press, Berkeley.

Steinberg, P. D., J. A. Estes, and F. C. Winter. 1995. Evolutionary consequences of food chain length in kelp forest communities. Proc. Nat. Acad. Sci. USA 92: 8145-8148.

Steinke, M., J. Stefels, and E. Stamhuis. 2006. Dimethyl sulfide triggers search behavior in copepods. Limnol. Oceanogr. 51: 1925-1930.

Stoecker, D. K., and J. J. Govoni, 1984. Food selection by young larval gulf menhaden (Brevoortia patronus). Mar. Biol. 80: 299-306.

Stoecker, D., R. R. L. Guillard, and R. M. Kavee. 1981. Selective predation by Favella ehrenbergii (Tintinnia) on and among dinoflagellates. Biol. Bull. 160: 136-145.

Swanson, R. L., J. E. Williamson, R. De Nys, N. Kumar, M. P. Bucknall, and P. D. Steinberg. 2004. Induction of settlement of larvae of the sea urchin Holopneustes purpurascens by histamine from a host alga. Biol. Bull. 206: 161-172.

Sykes, P. E., and M. E. Huntley. 1987. Acute physiological reactions of Calanus pacificus to selected dinoflagellates: direct observations. Mar. Biol. 94: 19-24.

Teegarden, G. J., and A. D. Cembella. 1996. Grazing of toxic dinoflagellates, Alexandrium spp., by adult copepods of coastal Maine: implications for the fate of paralytic shellfish toxins in marine food webs. J. Exp. Mar. Biol. Ecol. 196: 145-176.

Terlau, H., S. H. Heinemann, W. Stuhmer, M. Pusch, F. Conti, K. Imoto, and S. Numa. 1991. Mapping the site of block by tetrodotoxin and saxitoxin of sodium channel II. FEBS Lett. 293: 93-96.

Thuesen, E. V., K. Kogure, K. Hashimoto, and T. Nemoto. 1988. Poison arrowworms: a tetrodotoxin venom in the marine phylum Chaetognatha. J. Exp. Mar. Biol. Ecol. 116: 249-256.

Toledo, R. C., and C. Jared. 1995. Cutaneous granular glands and amphibian venoms. Comp. Biochem. Physiol. 111A: 1-29.

Trigo, J. R., K. S. Brown, Jr., L. Witte, T. Hartmann, L. Ludger, and L. E. S. Barata. 1996. Pyrrolizidine alkaloids: different acquisition and use patterns in Apocynaceae and Solanaceae feeding ithomiine butterflies (Lepidoptera: Nymphalidae). Biol. J. Linn. Soc. 58: 99-123.

Turner, J. T., and D. M. Anderson. 1983. Zooplankton grazing during dinoflagellate blooms in a Cape Cod embayment, with observations of predation upon tintinnids by copepods. Mar. Ecol. 4: 359-374.

Turner, J. T., G. J. Doucette, C. L. Powell, D. M. Kulis, B. A. Keafer, and D. M. Anderson. 2000. Accumulation of red tide toxins in larger size fractions of zooplankton assemblages from Massachusetts Bay, USA. Mar. Ecol. Prog. Ser. 203: 95-107.

Turriff, N., J. A. Runge, and A. D. Cambella. 1995. Toxin accumulation and feeding behaviour of the planktonic copepod Calanus finmarchicus exposed to the red-tide dinoflagellate Alexandrium excavatum. Mar. Biol. 123: 55-64.

Twarog, B. M., T. Hidaka, and H. Yamaguchi. 1972. Resistance to tetrodotoxin and saxitoxin in nerves of bivalve mollusks: a possible correlation with paralytic shellfish poisoning. Toxicon 10: 273-278.

Uye, S. 1986. Impact of copepod grazing on the red-tide flagellate Chattonella antiqua. Mar. Biol. 92: 35-43.

Uye, S., and K. Takamatsu. 1990. Feeding interactions between planktonic copepods and red-tide flagellates from Japanese coastal waters. Mar. Ecol. Prog. Ser. 59: 97-107.

Van Dolah, F. M. 2000. Marine algal toxins: origins, health effects, and their increased occurrence. Environ. Health Perspect. 108: 133-141.

Vickers, N. J., T. A. Christiansen, T. C. Baker, and J. G. Hildebrand. 2001. Odour-plume dynamics influence the brain's olfactory code. Nature 410: 466-470.

Weller, S. J., N. L. Jacobson, and W. E. Conner. 1999. The evolution of chemical defenses and mating systems in tiger moths (Lepidoptera: Arctiidae). Biol. J. Linn. Soc. 68: 557-578.

White, A. W. 1978. Paralytic toxins in the dinoflagellate Gonyaulax excavata and in shellfish. Bull. Fish. Res. Board Can. 35: 397-402.

White, A. W. 1980. Recurrence of kills of Atlantic herring Clupea harengus harengus caused by dinoflagellate toxins transferred through herbivorous zooplankton. Can. J. Fish. Aquat. Sci. 37: 2262-2265.

White, A. W. 1981. Sensitivity of marine fishes to toxins from the red-tide dinofiagellate Gonyaulax excavata and implications for fish kills. Mar. Biol. 65: 255-260.

Whittaker, R. H., and P. P. Feeny. 1971. Allelochemics: chemical interactions between species. Science 171: 757-770.

Williams, B. L., E. D. Brodie, Jr., and E. D. Brodie III. 2004. A resistant predator and its toxic prey: persistence of newt toxin leads to poisonous (not venomous) snakes. J. Chem. Ecol. 30: 1901-1919.

Wolfe, G. V., M. Steinke, and G. O. Kirst. 1997. Grazing-activated chemical defense in a unicellular alga. Nature 387: 894-897.

Wyatt, T., and J. Horwood. 1973. Model which generates red tides. Nature 244: 238-240.

Yamamori, K., M. Nakamura, T. Matsui, and T. J. Hara. 1988. Gustatory responses to tetrodotoxin and saxitoxin in fish: a possible mechanism for avoiding marine toxins. Can. J. Fish. Aquat. Sci. 45: 2182-2186.

Yamatogi, T., M Sakaguchi, M. Matsuda, S. Iwanaga, M. Iwataki, and K. Matsuoka. 2005. Effect on bivalve mollusks of a harmful dinoflagellate Hetercapsa circularisquama isolated from Omura Bay, Japan and its growth characteristics. Nippon Suisan Gakkaishi 71: 746-754.

Zimmer, R. K., and C. A. Butman. 2000. Chemical signaling processes in the marine environment. Biol. Bull. 198: 168-187.

Zimmer, R. K., D. W. Schar, R. P. Ferrer, P. J. Krug, L. B. Kats, and W. C. Michel. 2006. The scent of danger: tetrodotoxin (TTX) as an olfactory cue of predation risk. Ecol. Monogr. 76: 585-600.

Zimmer-Faust, R. K., and M. N. Tamburri. 1994. Chemical identity and ecological implications of a waterborne, larval settlement cue. Limnol. Oceanogr. 39: 1075-1087.

Zimmer-Faust, R. K., C. M. Finelli, N. D. Pentcheff, and D. S. Wethey. 1995. Odor plumes and animal navigation in turbulent water flow: a field study. Biol. Bull. 188: 111-116.

RICHARD K. ZIMMER (1,2*) AND RYAN P. FERRER (1)

(1) Department of Ecology and Evolutionary Biology, University of California, Los Angeles, California 90095-1606; and (2) Neurosciences Program and Brain Research Institute, University of California, Los Angeles, California 90095-1606

Received 9 May 2007; accepted 7 July 2007.

* To whom correspondence should be addressed: E-mail: z@biology.ucla.edu

Abbreviations: STX, saxitoxin; TTX, tetrodotoxin.
Table 1 Effects of neurotoxins and arginine on behavior of adult and
larval newts (Taricha torosa) (data are previously unpublished or taken
from Zimmer et al., 2006; Ferrer and Zimmer, 2007a,b)

                                              Number of animals
Life history    Compound and                  Hiding in  Having muscle
stage           concentration released        refuge     spasms

Larvae          [10.sup.-7] mol [l.sup.-1]    9          0
  (laboratory)    tetrodotoxin
                [10.sup.-7] mol [l.sup.-1]    1          0
                  saxitoxin
                [10.sup.-7] mol [l.sup.-1]    0          7
                  [mu]-conotoxin GIIIB
                [10.sup.-7] mol [l.sup.-1]    0          0
                  arginine
                [10.sup.-7] mol [l.sup.-1]    0          0
                  arginine + [10.sup.-7] mol
                  [l.sup.-1] tetrodotoxin
                None (tap water control)      0          0
Adults (field)  [10.sup.-5] mol [l.sup.-1]    0          0
                  arginine*
                None (filtered stream water)  0          0

                                              Number of animals
                                              Swimming
Life history    Compound and                  upstream   Not
stage           concentration released        to source  responding

Larvae          [10.sup.-7] mol [l.sup.-1]     0          1
  (laboratory)    tetrodotoxin
                [10.sup.-7] mol [l.sup.-1]     0          9
                  saxitoxin
                [10.sup.-7] mol [l.sup.-1]     0          3
                  [mu]-conotoxin GIIIB
                [10.sup.-7] mol [l.sup.-1]     0         10
                  arginine
                [10.sup.-7] mol [l.sup.-1]     0         10
                  arginine + [10.sup.-7] mol
                  [l.sup.-1] tetrodotoxin
                None (tap water control)       0         10
Adults (field)  [10.sup.-5] mol [l.sup.-1]    11          4
                  arginine*
                None (filtered stream water)   2         13

* Trials substituting fluorescent dye for arginine indicate a mean
concentration of 2.6 x [10.sup.-9] mol [l.sup.-1] in contact with adults
(see Ferrer and Zimmer, 2007a).

Table 2 Effects of tetrodotoxin (TTX) and saxitoxin (STX) on animal
behavior

Compound  Animal         Effect                          Source

TTX       Male puffer    Released by gravid female       Matsumura, 1995
            fish (Fugu     puffer fish and attracts
            niphobles)     sexually mature
                           conspecific males
          Marine         Present in the tissues of       Hwang et al.,
            snails         various prey species and        2004
            (Natica        stimulates feeding in
            spp.)          predatory snails
          California     Released by adult cannibals     Zimmer et al.,
            newt larva     and causes larval prey to       2006
            (Taricha       flee and hide in refuges
            torosa)
STX       Staghorn       Present in the tissues of       Kvitek, 1991
            sculpin        toxic butter clams and
            (Leptocotus    conditions feeding
            armatus)       aversion in predatory fish
          Sea otter      Present in the tissues of       Kvitek et al.,
            (Enhydra       toxic butter clams and          1991
            lutris)        alters feeding behavior
                           and diet of predatory otters
          Oystercatcher  Present in the tissues of       Kvitek and
            (Haematopus    toxic mussels and alters        Bretz, 2005
            bachmani)      feeding behavior, diet, and
                           distributions of predatory
                           birds
          Amphipod       Released by dinoflagellates     Camacho and
            (Hyalella      and stimulates feeding          Thacker, 2006
            azteca)        activity in amphipod grazers
COPYRIGHT 2007 University of Chicago Press
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2007 Gale, Cengage Learning. All rights reserved.

Article Details
Printer friendly Cite/link Email Feedback
Author:Zimmer, Richard K.; Ferrer, Ryan P.
Publication:The Biological Bulletin
Geographic Code:1USA
Date:Dec 1, 2007
Words:12233
Previous Article:Biological Bulletin virtual symposium: the neuroecology of chemical defense.
Next Article:Chemical defenses: from compounds to communities.
Topics:

Terms of use | Privacy policy | Copyright © 2021 Farlex, Inc. | Feedback | For webmasters |