Objective In neurons, sites of Ca2+ influx and Ca2+ sensors are located within 20-50 nm, in subcellular “Ca2+ nanodomains”. Such tight coupling is crucial for the functional properties of synapses and neuronal excitability. Two key players act together in nanodomains, coupling Ca2+ signal to membrane potential: the voltage-dependent Ca2+ channels (VDCC) and the large conductance Ca2+ and voltage-gated K+ channels (BK). BK channels are characterized by synergistic activation by Ca2+ and membrane depolarization, but the complex molecular mechanism underlying channel function is not adequately understood. Information about the pore region, voltage sensing domain or isolated intracellular domains has been obtained separately using electrophysiology, biochemistry and crystallography. Nevertheless, the specialized behavior of this channel must be studied in the whole protein complex at the membrane in order to determine the complete range of structures and movements critical to its in vivo function. Using a combination of genetics, electrophysiology and spectroscopy, our group has measured for the first time the structural rearrangements accompanying whole BK channel activation at the membrane. From this unique position, our first goal is to fully determine the real time structural dynamics underlying the molecular coupling of Ca2+, voltage and activation of BK channels in the membrane environment, its regulation by accessory subunits and channel effectors.BK subcellular localization and role in Ca2+ nanodomains make these channels perfect candidates as reporters of local changes in [Ca2+] restricted to specific nanodomains close to the neuronal membrane. In our laboratory we have created fluorescent variants of the channel that report BK activity induced by Ca2+ binding, or Ca2+ binding and voltage. Our second aim in this proposal is to optimize and deploy this novel optoelectrical reporters to study physiologically relevant Ca2+-induced processes both in cellular and animal mode Fields of science natural sciencesearth and related environmental sciencesgeologymineralogycrystallographynatural scienceschemical sciencesinorganic chemistryalkaline earth metalsnatural sciencesphysical sciencesopticsmicroscopysuper resolution microscopynatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsnatural sciencesphysical sciencesopticsspectroscopy Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Topic(s) ERC-CoG-2014 - ERC Consolidator Grant Call for proposal ERC-2014-CoG See other projects for this call Funding Scheme ERC-COG - Consolidator Grant Host institution UNIVERSIDAD DE LA LAGUNA Net EU contribution € 1 999 742,00 Address PADRE HERRERA S/N 38200 SAN CRISTOBAL DE LA LAGUNA Spain See on map Region Canarias Canarias Tenerife Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 1 999 742,00 Beneficiaries (1) Sort alphabetically Sort by Net EU contribution Expand all Collapse all UNIVERSIDAD DE LA LAGUNA Spain Net EU contribution € 1 999 742,00 Address PADRE HERRERA S/N 38200 SAN CRISTOBAL DE LA LAGUNA See on map Region Canarias Canarias Tenerife Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 1 999 742,00