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Caveolar microdomains as organizers of calcium signaling.

[Ca.sup.2+] is a major signaling molecule in both excitable and non-excitable cells, where it modulates a variety of cellular functions ranging from cell growth to differentiation to cell death. Across a wide spatial and temporal range, several [Ca.sup.2+] channels generate [Ca.sup.2+] signals that can last from microseconds to minutes. This broad range of [Ca.sup.2+] signals can be efficiently coordinated through organization of specific [Ca.sup.2+] channels, pumps, buffers, exchangers and protein scaffolds at common microdomains. Lipid rafts/ caveolae serve as such a plasma membrane (PM) microdomain wherein highly specific signaling molecules are assembled so as to efficiently execute a defined signaling event with precision. Unlike the membrane rafts, which are planar, 'Caveolae'--a raft subset represent flask/omega shaped membrane invaginations that ate widely expressed in a variety of cell types. Caveolae are cholesterol rich specialized PM domains with Caveolin1 (Cav1) as their major structural protein. These membrane domains represent a major cellular sub-compartment that facilitates various signal transduction events including [Ca.sup.2+] influx. Transient receptor potential canonical-1 (TRPC1) constitute an integral component of PM [Ca.sup.2+] channels that initiates store operated [Ca.sup.2+] entry (SOCE) following the depletion of endoplasmic reticulum (ER) [Ca.sup.2+]. One of the important questions regarding SOCE that has been actively pursued is about the molecular mechanism(s) whereby the status of the ER [Ca.sup.2+] store is communicated to the plasma membrane channels to initiate [Ca.sup.2+] influx. Recent, studies from several laboratories have identified the involvement of stromal interaction molecule-1(STIM1) in this process. STIM1 is expressed in the ER as a single transmembrane protein which can sense the changes in ER [Ca.sup.2+] levels. Following depletion of ER [Ca.sup.2+], STIM1 forms clusters at the ER-PM junctional regions, where it physically associates with PM channels and activates SOCE. Here we demonstrate the association of TRPC1 and STIM1 with caveolar compartments of the PM. Depletion of ER [Ca.sup.2+] stores enhanced the recruitment of TRPC1 protein to plasma membrane rafts and its interaction with STIM1. Disruption of caveolar domains by sequestering membrane cholesterol altered raft-associated TRPC1 localization, its interaction with STIM1 and eventually SOCE. Additionally, silencing of Cav1 severely reduced the PM association of TRPC1 and in cav1 knockout tissues; membrane raft association of TRPC1 was abolished. Altogether, our findings demonstrate activation of TRPC1 relies on its association with STIM1 and on the integrity of caveolar micro-domains. In conclusion, we propose that the association of TRPC1 with Cav1 is required for targeting the channel to specific PM compartments, where it functionally associates with its activator STIM1, thereby, providing a substantial evidence for caveolae as organizers of TRPC1 mediated [Ca.sup.2+] signaling.


We duly acknowledge grant support from the NSF (0548733) and the NIH (DE017102, 5P20RR017699) awarded to B.B.S anda ND-EPSCoR fellowship award to B.P.

Biswaranjan Pani, Hweiling Ong *, Xibao Liu *, Kristina Rauser, Virginia Achen, Indu Ambudkar * and Brij B Singh

Department of Biochemistry and Molecular Biology, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58201, * NIDCR, NIH, Bethesda, MD 20892
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Author:Pani, Biswaranjan; Ong, Hweiling; Liu, Xibao; Rauser, Kristina; Achen, Virginia; Ambudkar, Indu; Sin
Publication:Proceedings of the North Dakota Academy of Science
Article Type:Abstract
Geographic Code:1USA
Date:Apr 1, 2009
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