2.8.1. K*V*7 Channels

Amongst potassium channels, K*<sup>V</sup>* channels constitute the most diverse group with 12 known families [209]. Literature abounds on how various K*<sup>V</sup>* channels modulate nociception at different levels of the pain pathway [210]. The prototypical structural assembly of K*<sup>V</sup>* channels involves six transmembrane segments of which the first four (S1-S4) constitute the voltage-sensing domain (VSD) while the S5 and S6 segments constitute the pore through which K<sup>+</sup> ions pass [211,212]. Amongst others, the K*V*7 channel family has received immense attention in lieu of its amenability by GPCR modulation [213,214], with five known members (K*V*7.1– K*V*7.5) encoded by KCNQ1-5 genes [209]. Four monomers come together in a homo- or heterotetrameric configuration in a subunit-specific way to yield a functional K*V*7 channel [215]. The electrophysiological correlate of K*V*7 channel activity is a slowly deactivating, non-inactivating current that has an activation threshold below −60 mV. This conductance is also known as M current as it was originally described as a current that is suppressed by an activation of muscarinic acetylcholine receptors [216]. In nociceptors, these channels contribute majorly to the resting membrane potential [217]. K*V*7 channels are expressed in all functional parts of a first-order neuron which include free nerve endings, nodes of Ranvier, and the somata of dorsal root ganglion (DRG) neurons [218]. They regulate action potential (AP) firing, which is the basis for encoding of noxious stimuli in the pain pathway [219]. Enhancing K*V*7 currents exerts analgesic effects since hyperpolarizing the resting membrane potential of nociceptors decreases neuronal excitability [220,221]. Similarly, inhibiting K*V*7 currents is proalgesic since concomitant depolarization of the resting membrane potential enhances neuronal firing [222,223].
