Catalyst-like Modulation of Transitions States for CFTR Channel Opening and Closing: New Stimulation Strategy Exploits Nonequilibrium Gating

Csanády, László and Törőcsik, Beáta (2014) Catalyst-like Modulation of Transitions States for CFTR Channel Opening and Closing: New Stimulation Strategy Exploits Nonequilibrium Gating. JOURNAL OF GENERAL PHYSIOLOGY. pp. 1-53. ISSN 0022-1295

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Abstract

CFTR is the chloride ion channel mutated in cystic fibrosis (CF) patients. It is an ABC protein, and its resulting cyclic nonequilibrium gating mechanism sets it apart from most other ion channels. The most common CF mutation (ΔF508) impairs folding of CFTR, but also channel gating, reducing open probability (Po). This gating defect must be addressed to effectively treat CF. Combining single-channel and macroscopic current measurements in inside-out patches we show here that the two effects of NPPB (5-Nitro-2-(3-phenylpropylamino)benzoate) on CFTR, pore block and gating stimulation, are independent, suggesting action at distinct sites. Furthermore, detailed kinetic analysis revealed that NPPB potently increases Po, also of ΔF508 CFTR, by affecting the stability of gating transition states. This finding is unexpected, since for most ion channels, which gate at equilibrium, altering transitionstate stabilities has no effect on Po: rather, agonists usually stimulate by stabilizing open states. Our results highlight how for CFTR, due to its unique cyclic mechanism, gating transition states determine Po and offer strategic targets for potentiator compounds to achieve maximal efficacy.

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