Signature and Pathophysiology of Non-canonical Pores in Voltage-Dependent Cation Channels

Abstract

Opening and closing of voltage-gated cation channels allows the regulated flow of cations such as Na(+), K(+), and Ca(2+) across cell membranes, which steers essential physiological processes including shaping of action potentials and triggering Ca(2+)-dependent processes. Classical textbooks describe the voltage-gated cation channels as membrane proteins with a single, central aqueous pore. In recent years, however, evidence has accumulated for the existence of additional ion permeation pathways in this group of cation channels, distinct from the central pore, which here we collectively name non-canonical pores. Whereas the first non-canonical pores were unveiled only after making specific point mutations in the voltage-sensor region of voltage-gated Na(+) and K(+) channels, recent evidence indicates that they may also be functional in non-mutated channels. Moreover, several channelopathies have been linked to mutations that cause the appearance of a non-canonical ion permeation pathway as a new pathological mechanism. This review provides an integrated overview of the biophysical properties of non-canonical pores described in voltage-dependent cation channels (KV, NaV, Cav, Hv1, and TRPM3) and of the (patho)physiological impact of opening of such pores.

Mutations in the voltage‐sensing domain affect the alternative ion permeation pathway in the TRPM3 channel

“…; Held et al . ). These results are also in line with studies of the proton channel H V 1 that possesses a natural non‐canonical pore that can be blocked by introduction of an arginine at position R4 in the S4 voltage sensor (Tombola et al .…”

“…Further, mutations of the arginines at position R3 in Na v 1.4, Na v 1.5 and Ca v 1.1 were also associated with non‐canonical pore currents and the above‐mentioned diseases (for review see Held et al . ). Finally, arginine mutations at position R4 of hK V 7.2 were connected to neuronal hyperexcitability (Miceli et al .…”

“…A similar mechanism has been proposed for the opening of the non‐canonical pore in voltage‐gated K + , Na + and Ca 2+ channels as well as for the pore opening of the VSD protein H V 1 during membrane depolarization (for review see Held et al . ). The S4 segment of voltage‐gated K + , Na + and Ca 2+ channels contains a series of at least three positively charged residues, while the transmembrane segments S1, S2 and S3 contain organized structures of highly conserved negatively charged amino acids that appear to be involved in the stabilization of S4 in different conformational states (Pless et al .…”

“…), indicating the pathophysiological relevance of non‐canonical ion permeation pathways (reviewed in Held et al . ). Recently, we have shown the presence of a non‐canonical pore in TRPM3 (Vriens et al .…”

“…The presence of a 'non-canonical' ion permeation pathway was first described in Shaker K + channels, in which neutralization of the first gating charge in S4 allowed the permeation of protons or metal cations through an ionic gap in the VSD of the channel (Starace & Bezanilla, 2004;Tombola et al 2005). Subsequently, similar non-canonical pores were described in disease-causing mutants of voltage-gated K + , Na + and Ca 2+ channels (Sokolov et al 2007;Gosselin-Badaroudine et al 2012;Miceli et al 2012;Wu et al 2012), indicating the pathophysiological relevance of non-canonical ion permeation pathways (reviewed in Held et al 2016). Recently, we have shown the presence of a non-canonical pore in TRPM3 (Vriens et al 2014), a member of the transient receptor potential (TRP) superfamily, which shows a similar architecture to voltage-gated K + , Ca 2+ and Na + channels.…”