Mechanisms of gating in physiological responses of pH sensitive tandem pore potassium channels. (360G-Wellcome-079863_Z_06_Z)

£193,590

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