Structural insights into the function, dysfunction and modulation of Kv3 channels

The third subfamily of voltage-gated K⁺ (Kv) channels includes four members, Kv3.1, Kv3.2, Kv3.3 and Kv3.4. Fast gating and activation at relatively depolarized membrane potentials allows Kv3 channels to be major drivers of fast action potential repolarization in the nervous system. Consequently, they help determine the fast-spiking phenotype of inhibitory interneurons and regulate fast synaptic transmission at glutamatergic synapses and the neuromuscular junction. Recent studies from our group and a team of collaborators have used cryo-EM to demonstrate the surprising gating role of the Kv3.1 cytoplasmic T1 domain, the structural basis of a developmental epileptic encephalopathy caused by the Kv3.2-C125Y variant and the mechanism of action of positive allosteric modulators involving unexpected interactions and conformational changes in Kv3.1 and Kv3.2. Furthermore, our recent work has shown that Kv3.4 regulates use-dependent spike broadening in a manner that depends on gating modulation by phosphorylation of the channel's N-terminal inactivation domain, which can impact activity-dependent synaptic facilitation. Here, we review and integrate these studies to provide a perspective on our current understanding of Kv3 channel function, dysfunction and pain modulation in the nervous system.