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Transmembrane Signaling Group

Molecular Make-up, Physiological Roles & Epigenetic Regulation of Signal Transduction Mechanisms

Research Summary

Our laboratory has a broad set of interests that include:

  • Molecular mechanism of activation and physiological roles of heterotrimeric G proteins;
  • Molecular makeup, mechanism of activation and physiological roles of the mammalian TRPC channels discovered by us in 1995-1996.

Within the above mentioned areas, we are currently focusing on:

  • Describing at the atomic level the interface between a GPCR (rhodopsin) and its cognate G protein (transducin). We use a combination of genetic engineering, purification of recombinant protein and hard core X-ray crystallography. This project, which is just beginning, addresses one of the most important mysteries in the field of signal transduction by G proteins: the molecular mechanism by which the GPCR triggers the exchange of GTP for GDP and the changes that lead from GTP binding to G-alpha subunit activation. GPCRs constitute the largest gene family in the mammalian genome and are targets of innumerable medicines used to control hypertension, migraines, acid secretion in the stomach to name a few. In spite of their importance it is still not known by what molecular mechanism any of the GPCRs activates its cognate G protein.
  • Elucidating at the molecular-biochemical level how the interplay between the newly discovered Orai proteins and the TRPC channels forms the so-called Store Operated Calcium Entry (SOCE) channels. We are testing the hypothesis that Orai and TRPCs form obligate heteromeric complexes activated by the store depletion phenomenon. SOCE is a universal phenomenon common to excitable and non-excitable cells. Cellular responses that extend from memory consolidation in neurons to regulation of gene expression in T cells depend on SOCE. Knockout studies have shown that both Orai and TRPCs participate in SOCE, yet the molecular makeup of the SOCE channels remains a mystery. These studies are done in close collaboration with David Armstrong ("/Rhythmyx/assembler/render?sys_contentid=52833&sys_revision=1&sys_variantid=1173&sys_context=0&sys_authtype=0&sys_siteid=&sys_folderid=" sys_dependentvariantid="1173" sys_dependentid="52833" inlinetype="rxhyperlink" rxinlineslot="103" sys_dependentid="52833" sys_siteid="" sys_folderid="") who leads the Membrane Signaling Group ("/Rhythmyx/assembler/render?sys_contentid=52833&sys_revision=1&sys_variantid=1173&sys_context=0&sys_authtype=0&sys_siteid=&sys_folderid=" sys_dependentvariantid="1173" sys_dependentid="52833" inlinetype="rxhyperlink" rxinlineslot="103" sys_dependentid="52833" sys_siteid="" sys_folderid="") of the Laboratory of Neurobiology ("/Rhythmyx/assembler/render?sys_contentid=52832&sys_revision=1&sys_variantid=1173&sys_context=0&sys_authtype=0&sys_siteid=&sys_folderid=" sys_dependentvariantid="1173" sys_dependentid="52832" inlinetype="rxhyperlink" rxinlineslot="103" sys_dependentid="52832" sys_siteid="" sys_folderid="").
  • Physiological roles of G protein alpha subunits and TRPC channels as seen in the living animal are pursued in collaborative studies in which one or more of these genes have been disrupted and/or mutated (classical and conditional knock-out and knock-in mice).

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