UCSF

Voltage-gated ion channels (VGICs) use voltage sensing domains (VSD) to sense the change in electrical potential across biological membranes and alter the open probability of a central channel. VSDs are composed of a four helix bundle in which one helix carries charged residues that move in response to changes in transmembrane electric field. Voltage sensors usually adopt a ‘resting state’ when the membrane is at ‘resting potential’, approximately -80 mV for most plasma membranes. As the membrane potential vanishes during depolarization - such as during the first phase of an action potential - so does the downwards force on the cationic side chains causing them to move across the membrane. This conformational change is conveyed to the central pore, which dilates to allow the diffusion of ions down their electrochemical gradients. The exact nature of this conformational change has been the subject of decades of biophysical investigation, though to this date only a few structural examples exist of voltage sensors in multiple conformations. Using a combination of single particle cryogenic electron microscopy (cryoEM) and electrophysiology, I have determined how a family of intracellular VGICs - two-pore channels (TPCs) - respond to changes in membrane potential providing new insights into the biophysics of voltage activation.