Determining the role of the mechano-activated potassium channel TRAAK at nodes of Ranvier

Abstract Action potential propagation through nodes of Ranvier is central to nervous system function. Understanding this process is essential for developing improved treatments for nodal pathologies of electrical signaling including multiple sclerosis, Guillain-Barré syndrome, stroke, spinal injury, and glaucoma. Saltatory conduction—the jumping of the action potential from one node to the next—has been described since its discovery as a purely electrical phenomenon. This proposal aims to investigate whether it is also fundamentally mechanical in nature. The mechano-activated two-pore domain potassium channel TRAAK is exclusively expressed at nodes of Ranvier. TRAAK is insensitive to voltage, but acutely tuned to membrane tension, with cell swelling increasing TRAAK-mediated potassium currents up to one hundred-fold. Still, whether mechanical activation of TRAAK is relevant to spike propagation is unknown. Using a combination of organic chemistry, molecular biophysics, and neurophysiology, this proposal will examine how mechanically activated TRAAK currents contribute to action potential propagation, speed, and reliability. To selectively control TRAAK channels, photoswitchable tethered ligands (PTLs) will be designed, synthesized, and optimized for maximal spatiotemporally precise block of TRAAK current. Screening of PTL tethering sites in leak and mechano-activated open TRAAK channels will enable the identification of state-specific PTL·Cys-TRAAK pairs and the precise modulation of basal and/or mechano-activated TRAAK currents. Using these tools, TRAAK's contributions to action potential propagation will be characterized in myelinated optic nerve under typical conditions and in response to mechanical perturbation. These experiments will both elucidate the role of TRAAK in spike propagation and, potentially, demonstrate that mechanical force is central to node repolarization, with broad implications for the treatment of nodal pathologies and the field of neuronal communication as a whole.