Mechanisms of gating in physiological responses of pH sensitive tandem pore potassium channels. (360G-Wellcome-079863_Z_06_Z)
Acid sensitive potassium channels of the tandem pore family are thought to sense extracellular pH through a His residue at the pore mouth. Our studies on TASK-1 show that the wild type selectivity filter is essential for the response to acidification, which probably involves gating at the selectivity filter in response to protonation. We shall test the generality of this mechanism using site directed mutagenesis and electrophysiological techniques to study both acid-(TASK-3 and TWIK-1) and alkaline-sensitive (TASK-2) channels. We shall use TASK-3 to investigate how microscopic kinetics is altered by acidification, investigating possible state dependence of the effect of protons. Modulation of channels by a variety of factors is important in the physiological function of these channels, many factors actingthrough depletion of phosphatidylinositol bis phosphate (PIP2). We shall study state dependent access of intracellular blocking agents to ask whether channels open and close at the inner pore mouth, as do other, less closely related K+ channels. We shall study mutants of transmembrane domains M2 and M4, including A237T (at the cytoplasmic end of the transmembrane domain M4), which we have shown to increase channel open state probability.
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Grant Details
Amount Awarded | 193590 |
Applicant Surname | Stanfield |
Approval Committee | Physiological Sciences Funding Committee |
Award Date | 2006-04-30T00:00:00+00:00 |
Financial Year | 2005/06 |
Grant Programme: Title | Project Grant |
Internal ID | 079863/Z/06/Z |
Lead Applicant | Prof Peter Stanfield |
Partnership Value | 193590 |
Planned Dates: End Date | 2009-08-31T00:00:00+00:00 |
Planned Dates: Start Date | 2006-06-01T00:00:00+00:00 |
Recipient Org: Country | United Kingdom |
Region | West Midlands |