Objetivo 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. Ámbito científico natural sciencesbiological sciencesbiochemistrybiomoleculesnatural scienceschemical sciencesinorganic chemistryalkaline earth metalsmedical and health sciencesbasic medicinepharmacology and pharmacy Programa(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) Tema(s) FP7-PEOPLE-2012-CIG - Marie-Curie Action: "Career Integration Grants" Convocatoria de propuestas FP7-PEOPLE-2012-CIG Consulte otros proyectos de esta convocatoria Régimen de financiación MC-CIG - Support for training and career development of researcher (CIG) Coordinador THE HEBREW UNIVERSITY OF JERUSALEM Aportación de la UE € 100 000,00 Dirección EDMOND J SAFRA CAMPUS GIVAT RAM 91904 Jerusalem Israel Ver en el mapa Tipo de actividad Higher or Secondary Education Establishments Contacto administrativo Hani Ben Yehuda (Ms.) Enlaces Contactar con la organización Opens in new window Sitio web Opens in new window Coste total Sin datos
