Rietmeijer, R. A. | Search bioRxiv

bioRxiv2021

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

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.

biophysics↗

bioRxiv2020

Ultrasound activates mechanosensitive TRAAK K+ channels directly through the lipid membrane

Ultrasound modulates the electrical activity of excitable cells and offers advantages over other neuromodulatory techniques; for example, it can be non-invasively transmitted through skull and focused to deep brain regions. However, the fundamental cellular, molecular, and mechanistic bases of ultrasonic neuromodulation are largely unknown. Here, we demonstrate ultrasound activation of the mechanosensitive K+ channel TRAAK with sub-millisecond kinetics to an extent comparable to canonical mechanical activation. Single channel recordings reveal a common basis for ultrasonic and mechanical activation with stimulus-graded destabilization of long-duration closures and promotion of full conductance openings. Ultrasonic energy is transduced to TRAAK directly through the membrane in the absence of other cellular components, likely increasing membrane tension to promote channel opening. We further demonstrate ultrasonic modulation of neuronally expressed TRAAK. These results suggest mechanosensitive channels underlie physiological responses to ultrasound and provides a framework for developing channel-based sonogentic actuators for acoustic neuromodulation of genetically targeted cells.

neuroscience↗