DYNAMIC CAVEOLIN-CAVEOLAE-STEROID SIGNALING COMPLEXES

University Of Denver, Denver CO

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Abstract

Dynamic cellular microcircuits that organize and regulate signal transduction in hormone-responsive cells are apparently localized in plasma membrane microdomains that are enriched in cholesterol and other complex lipids. In mammalian cells these membrane microdomains have been caveolae, rafts or DIGS (detergent- insoluble glycolipid-enriched complexes). One novel possibility that has not yet been addressed is that growth-promoting steroid hormones may interact with caveolar structures-directly by binding to caveolar receptors, or indirectly by affecting cholesterol biosynthesis and (as a consequence) membrane cholesterol and caveolar structure and function. Direct or indirect effects of hormone on caveolae may alter the distribution of signaling proteins (G proteins and other receptor complex proteins) in such a way that second messenger (cyclic AMP) levels are modulated as a result of altered adenylyl cyclase activity. By taking advantage of the unique characteristics of the Xenopus oocyte system, the cellular relevance of previously reported effects of caveolin 'scaffolding domains' on G protein action will also be examined by microinjection of synthetic scaffolding domain peptides, alone and in combination with extracellular application of inducing hormones, to test if increased levels of scaffolding peptides might be sufficient to trigger the caveolar microcircuit and either elicit the cell division response or potentiate the inducing actions of hormone. In addition, molecular cloning and sequencing techniques will be used to determine whether amphibian caveolin is another member of the existing mammalian caveolin gene family, or if the hormone effects and role for caveolae observed in the amphibian system might be due to the function of an as yet unidentified caveolin protein subtype. Results of these experiments will better explain the interplay between membrane lipids, caveolar proteins and steroid hormones in facilitating transmembrane signaling in hormone-responsive cells.