Structure and Chemical Biology of Mechanosensitive Ion Channels

Orateur : Marco LOLICATO (Cardiovascular Research Institute, University of California, San Francisco, United States)

Polymodal thermo- and mechanosensitive two-pore domain potassium (K2P) channels of the TREK subfamily generate ‘leak’ currents that regulate neuronal excitability, respond to lipids, temperature and mechanical stretch, and influence pain, temperature perception and anaesthetic responses. These dimeric voltage-gated ion channel (VGIC) superfamily members have a unique topology comprising two pore-forming regions per subunit. In contrast to other potassium channels, K2P channels use a selectivity filter ‘C-type’ gate as the principal gating site. We have studied the molecular basis of selectivity and gating in the mechanosensitive members of the K2P family, TREK-1 and TRAAK, unraveling the mechanism of channel activation by gain-of-function mutants or small molecule binding. Our data suggest that the activation of these channels depends on concerted conformational changes both at the level of the selectivity filter and in the transmembrane region.

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