Allosteric mechanisms of Ca activated K channel gating

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DESCRIPTION (provided by the applicant): Ion channels dynamically regulate membrane permeability through their ability to open and close (gate) in response to various stimuli. Progress has been made in identifying and characterizing functional components of channel proteins that are involved in this gating process including "sensors" that detect stimuli, and "gates" that regulate the flow of ions through the channel pore. However the conformational events and interactions that link the action of sensors and gates remain largely unknown and are likely to be of fundamental importance in understanding how channels normally work and how they are modulated by endogenous factors, drugs or disease. To determine the nature of communication between sensors and gates I have previously studied (in the laboratory of Richard Aldrich) the function of a large conductance Ca2+ -activated K channel (mSlo); a channel that senses both voltage and intracellular Ca2+. An allosteric mechanism exists by which the activation of sensors and the opening of the pore appear to represent conformationally distinct events that strongly influence each other but can occur in isolation. mSlo offers a unique opportunity for studying sensor/gate communication. By studying mSlo under extreme conditions and taking advantage of particular kinetic and steady state properties of this channel we are able to study, in isolation, sensor activation, channel opening and the interaction between sensor and gate. Moreover, the methods and analytical tools developed previously for WT channels can now be applied to mutant mSlo channels to identify residues that are involved in sensor/gate communication. The results will be important not only for understanding the gating of mSlo but also for elucidating the coupling between sensors and gates in other Ky channel.