Objective The somatosensory system detects and integrates a large array of noxious stimuli of highly divergent nature. Members of the transient receptor potential (TRP) ion channel family play a pivotal role in the detection of innocuous and noxious stimuli, of both physical and chemical nature. Thus, elucidating the gating mechanisms of these channels is essential for our understanding of somatosensation and nociception. Taken the polymodal nature of those somatosensory TRP channels, our overall goal is to provide a comprehensive understanding of their activation mechanisms as evoked by various stimuli. TRPV1, a member of this family, detects a variety of pain-evoking molecules such as vanilloids (capsaicin), protons and animal peptide toxins. This activity is mediated by at least two distinct channel regions; each binds different set of activators. Despite its central role in pain perception, our knowledge of TRPV1 molecular mechanism of action is limited. Here, we propose to examine the stoichiometry and allosteric regulation of TRPV1 activation through its two distinct binding regions. Our working hypothesis is that because TRPV1 is required to detect and react to a large range of noxious stimuli, each of its ligand-binding regions evolved to induce a defined activation mechanism. We will use concatemeric rat TRPV1 harboring subunit-specific mutants, which will be expressed in heterologous systems. We will analyze for changes in TRPV1 activation by various ligands using specific electrophysiological assays designed to measure channel gating, combined with calcium imaging and biochemical assays. Overall, the proposed study will identify the allosteric regulatory mechanisms by which TRPV1 is activated through its distinct ligand-binding regions, mechanisms that ultimately underlie the detection of noxious stimuli and pain perception. In whole, this study will facilitate the rational design of analgesics drugs, specifically targeting ligand-binding sites on pain receptors. Fields of science natural sciencesbiological sciencesbiochemistrybiomoleculesnatural scienceschemical sciencesinorganic chemistryalkaline earth metalsmedical and health sciencesbasic medicinepharmacology and pharmacy Programme(s) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Topic(s) FP7-PEOPLE-2012-CIG - Marie-Curie Action: "Career Integration Grants" Call for proposal FP7-PEOPLE-2012-CIG See other projects for this call Funding Scheme MC-CIG - Support for training and career development of researcher (CIG) Coordinator THE HEBREW UNIVERSITY OF JERUSALEM Address Edmond j safra campus givat ram 91904 Jerusalem Israel See on map Activity type Higher or Secondary Education Establishments Administrative Contact Hani Ben Yehuda (Ms.) Links Contact the organisation Opens in new window Website Opens in new window EU contribution No data
