Pressure and ultrasound activate mechanosensitive TRAAK K⁺channels through increased membrane tension

Abstract

TRAAK is a mechanosensitive two-pore domain K+ (K2P) channel found in nodes of Ranvier within myelinated axons. It displays low leak activity at rest and is activated up to one hundred-fold by increased membrane tension. Structural and functional studies have led to physical models for channel gating and mechanosensitivity, but no quantitative analysis of channel activation by tension has been reported. Here, we use simultaneous patch-clamp recording and fluorescent imaging to determine the tension response characteristics of TRAAK. TRAAK shows high sensitivity and a broad response to tension spanning nearly the entire physiologically relevant tension range. This graded response profile distinguishes TRAAK from similarly low-threshold mechanosensitive channels Piezo1 and MscS, which activate in a step-like fashion over a narrow tension range. We further use patch imaging to show that ultrasonic activation of TRAAK and MscS is due to increased membrane tension. Together, these results provide mechanistic insight into TRAAK tension gating, a framework for exploring the role of mechanosensitive K+ channels at nodes of Ranvier, and biophysical context for developing ultrasound as a mechanical stimulation technique for neuromodulation.

Ultrasound system for precise neuromodulation of human deep brain circuits

“…17,18 Further research is needed to fully elucidate the mechanisms underpinning TUS and optimise stimulation parameters. A multiplicity of factors will likely influence the neuromodulatory effects of TUS, including the relative proportions of excitatory and inhibitory neurons within a target structure, 24 the distribution of mechanosensitive cation channels along those neurons, 25,26 and the morphology of the neuronal bodies and axons. 27 The exact contribution of these factors has yet to be established for the range of ultrasound parameters used in vivo, but as our knowledge increases, these data can be used to optimise TUS parameters based on the unique properties of deep brain structures, potentially enhancing the efficacy and specificity of the technique.…”