title: 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.
authors.affiliation: Laboratory of Experimental Gynecology, KU Leuven, Herestraat 49, Box 611, 3000, Leuven, Belgium.|Laboratory of Ion Channel Research and TRP Research Platform Leuven (TRPLe), KU Leuven, Herestraat 49, Box 802, 3000, Leuven, Belgium.
authors.forename: Katharina
authors.initials: K
authors.lastname: Held
authors.affiliation: Laboratory of Ion Channel Research and TRP Research Platform Leuven (TRPLe), KU Leuven, Herestraat 49, Box 802, 3000, Leuven, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: Voets
authors.affiliation: Laboratory of Experimental Gynecology, KU Leuven, Herestraat 49, Box 611, 3000, Leuven, Belgium. Joris.Vriens@med.kuleuven.be.
authors.forename: Joris
authors.initials: J
authors.lastname: Vriens
mesh_terms: D000818:Animals; D002412:Cations / Q000378:metabolism; D053447:Channelopathies / Q000503:physiopathology; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology*; D007473:Ion Channels / Q000502:physiology*
chemical_list: D002412:Cations; D007473:Ion Channels
keywords: Alternative ionic pathway; Cav; HV1 and TRPM3; KV; NaV; Voltage-dependent cation channels