title: A novel current pathway parallel to the central pore in a mutant voltage-gated potassium channel.
abstract: Voltage-gated potassium channels are proteins composed of four subunits consisting of six membrane-spanning segments S1-S6, with S4 as the voltage sensor. The region between S5 and S6 forms the potassium-selective ion-conducting central α-pore. Recent studies showed that mutations in the voltage sensor of the Shaker channel could disclose another ion permeation pathway through the voltage-sensing domain (S1-S4) of the channel, the ω-pore. In our studies we used the voltage-gated hKv1.3 channel, and the insertion of a cysteine at position V388C (Shaker position 438) generated a current through the α-pore in high potassium outside and an inward current at hyperpolarizing potentials carried by different cations like Na(+), Li(+), Cs(+), and NH(4)(+). The observed inward current looked similar to the ω-current described for the R1C/S Shaker mutant channel and was not affected by some pore blockers like charybdotoxin and tetraethylammonium but was inhibited by a phenylalkylamine blocker (verapamil) that acts from the intracellular side. Therefore, we hypothesize that the hKv1.3_V388C mutation in the P-region generated a channel with two ion-conducting pathways. One, the α-pore allowing K(+) flux in the presence of K(+), and the second pathway, the σ-pore, functionally similar but physically distinct from the ω-pathway. The entry of this new pathway (σ-pore) is presumably located at the backside of Y395 (Shaker position 445), proceeds parallel to the α-pore in the S6-S6 interface gap, ending between S5 and S6 at the intracellular side of one α-subunit, and is blocked by verapamil.
authors.affiliation: Institute of Applied Physiology, Ulm University, Ulm, Germany.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Prütting
authors.forename: Stephan
authors.initials: S
authors.lastname: Grissmer
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D019556:COS Cells; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002414:Cations, Monovalent; D002522:Chlorocebus aethiops; D006801:Humans; D017136:Ion Transport / Q000187:drug effects / Q000502:physiology; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020125:Mutation, Missense; D017434:Protein Structure, Tertiary; D014700:Verapamil / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D002414:Cations, Monovalent; D051664:Kv1.3 Potassium Channel; D014700:Verapamil