Cell 'caves' harbor clues to diseases.

Just as the probing of a new cave's mineral deposits can yield discoveries richer than the finding of the cave itself, the identification of the chemicals inside cellular chambers called caveolae is proving a mother lode for researchers.

Last year, cell biologists for the first time isolated these "tiny caves" from the surfaces of cells (SN: 8/28/93, p.143). At the time, not everyone was sure these membranous vesicles were true subcellular compartments, or organelles. But now, using two methods and two types of tissue, two research teams have reached similar conclusions. "This is an organelle, and it has a lot of interesting proteins," says Richard G.W. Anderson, who heads one team at the University of Texas Southwestern Medical Center at Dallas.

The protein that forms these vesicles -- caveolin -- is just one of many biologically important molecules found there, adds Michael P. Lisanti, who led the second group, based at the Whitehead Institute for Biomedical Research in Cambridge, Mass.

Lisanti and his colleagues have demonstrated that caveolae contain molecules implicated in the abnormal buildup of fatlike substances along blood vessels. Other constituents of caveolae play a role in tissue damage related to diabetes and in the disintegration of muscle in Duchenne muscular dystrophy, they report in the July 1 JOURNAL OF CELL BIOLOGY.

For their studies, Lisanti and his colleagues refined their initial purification procedures so they could isolate larger quantities of caveolae, this time from lung tissue rather than from cells grown in the laboratory. As a result, the group could systematically identify the protein components of these compartments, Lisanti explains.

Typically, scientists studying new organelles expect to find novel proteins inside them. "But we found what others had found in a different context, molecules important to the development of major human diseases," says Lisanti.

For example, other scientists had determined that CD36, a docking site for oxidized low-density lipoproteins, can lead to the unwanted cholesterol plaques that clog arteries. CD36 is concentrated inside caveolae, Lisanti's group reports. Also, in diabetics, the accumulation of substances altered by prolonged exposure to blood sugar can damage kidneys, the retina, and other tissues. These harmful substances also deposit inside caveolae, Lisanti says.

In the same journal, Anderson's group reports finding at least 30 proteins concentrated in caveolae. Using a biochemical approach, they purified caveolae from smooth muscle cells of chicken gizzards. These chambers were rich in proteins that use a specific chemical anchor (called glycosylphosphatidylinositol or GPI) to stick to the cell membrane, the Dallas researchers note.

It seems that caveolae can open, take in molecules from outside the cell, then close. They may move, process, or finally release those substances or their by-products. Thus, caveolae may help distribute proteins throughout the cell. At other times, these tiny caves may sequester molecules, Anderson says.

Some of those molecules are known cellular signals; others are suspected of carrying particular messages. "It suggests that caveolae are a central place for processing signals," says Lisanti.

One enzyme, protein kinase C, seems to help regulate the uptake of small molecules by caveolae, Anderson and Lisanti say. If researchers can eventually control the opening and closing of caveolae and the passage of substances into these chambers and thus into cells, the two scientists expect caveolae will prove valuable gateways for new drugs.

Toward that end, Douglas M. Lublin of Washington University School of Medicine in St. Louis has begun to elaborate what determines whether proteins enter caveolae. He finds that the GPI anchor is sufficient for some proteins to gain access, while others need to append two fatty-acid side chains to their structures. His work will appear in the July 15 JOURNAL OF CELL BIOLOGY.