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bioRxiv · 10.1101/2021.06.04.447000

Physical basis for distinct basal and mechanically-gated activity of the human K+ channel TRAAK

Rietmeijer, R. A.·Sorum, E.·Li, B.·Brohawn, S. G.
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Abstract

TRAAK is a mechanosensitive two-pore domain K+ (K2P) channel localized to nodes of Ranvier in myelinated neurons. TRAAK deletion in mice results in mechanical and thermal allodynia and gain-of-function mutations cause the human neurodevelopmental disorder FHEIG. TRAAK displays basal and stimulus-gated activities typical of K2Ps, but the mechanistic and structural differences between these modes are unknown. Here, we demonstrate that basal and mechanically-gated openings are distinguished by their conductance, kinetics, and structure. Basal openings are low conductance, short duration, and occur through a channel with an interior cavity exposed to the surrounding membrane. Mechanically-gated openings are high conductance, long duration, and occur through a channel that is sealed to the surrounding membrane. Our results explain how dual modes of activity are produced by a single ion channel and provide a basis for the development of state-selective pharmacology with the potential to treat disease.

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Rietmeijer, R. A., Sorum, E., Li, B., Brohawn, S. G.. 2021-06-06. Physical basis for distinct basal and mechanically-gated activity of the human K+ channel TRAAK. https://doi.org/10.1101/2021.06.04.447000

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