Timing is everything: structural insights into the disease-linked Kv3 channels controlling fast action-potential firing in the brain

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  Fig. 1. Kv3 channel structure, function and gating. A (i) Kv3 channels can be located at the Axon Initial Segment (AIS), along the axon, proximal dendrites and at presynaptic terminals of neurons where they (ii) help shape the ability of the neuron to sustain high frequency trains of action potentials and control neurotransmitter release. Insert shows a single action potential expanded view indicating the impact of Kv3 channels on the action potential waveform driving fast repolarization and keeping refractory periods brief. B Schematic of Kv3 channel architecture from above with the central ion conducting pore together with a topology map of a single subunit showing the six transmembrane (TM) domains, N- and C-termini, Voltage-Sensor Domain (VSD), pore helix (PH) and pore lining domain incorporating S5-S6. Four such subunits assemble as tetramers to form a functional channel. Approximate locations of confirmed disease-linked mutations are indicated by colored circles for each Kv3 channel; semicircles indicate coincident mutations in two of the four conserved arginines (R3 and R4) in S4 in Kv3.1 and Kv3.3. C–E Cryo-EM-determined structural representations of Kv3.1 adapted from Chi et…