title: Inhibition of the K+ channel kv1.4 by acidosis: protonation of an extracellular histidine slows the recovery from N-type inactivation.
abstract: 1. Acidosis alters the transient outward current, ito, in the heart. We have studied the mechanism underlying the effect of acidosis on one of the K+ channels, Kv1.4 (heterologously expressed in Xenopus laevis oocytes), known to underlie ito. 2. At pH 6.5, wild-type Kv1.4 current was inhibited during repetitive pulsing, in part as a result of a slowing of recovery from N-type inactivation. 3. Acidosis still caused slowing of recovery after deletion of just one (either the first or second) of the N-terminal inactivation ball domains. However, deletion of both the N-terminal inactivation ball domains greatly reduced the inhibition. 4. As well as the N-terminus, other parts of the channel are also required for the effect of acidosis, because, whereas the transfer of the N-terminus of Kv1.4 to Kv1.2 conferred N-type inactivation, it did not confer acidosis sensitivity. 5. Replacement of an extracellular histidine with a glutamine residue (H508Q) abolished the slowing of recovery by acidosis. Reduction of C-type inactivation by raising the bathing K+ concentration or by the mutation K532Y also abolished the slowing. 6. It is concluded that binding of protons to H508 enhances C-type inactivation and this causes a slowing of recovery from N-type inactivation and, thus, an inhibition of current during repetitive pulsing.
authors.affiliation: Schools of Biomedical Sciences and Biochemistry and Molecular Biology, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: T W
authors.initials: TW
authors.lastname: Claydon
authors.forename: M R
authors.initials: MR
authors.lastname: Boyett
authors.forename: A
authors.initials: A
authors.lastname: Sivaprasadarao
authors.forename: K
authors.initials: K
authors.lastname: Ishii
authors.forename: J M
authors.initials: JM
authors.lastname: Owen
authors.forename: H A
authors.initials: HA
authors.lastname: O'Beirne
authors.forename: R
authors.initials: R
authors.lastname: Leach
authors.forename: K
authors.initials: K
authors.lastname: Komukai
authors.forename: C H
authors.initials: CH
authors.lastname: Orchard
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D005260:Female; D005289:Ferrets; D006639:Histidine; D006863:Hydrogen-Ion Concentration; D051665:Kv1.4 Potassium Channel; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009865:Oocytes / Q000502:physiology; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000737:chemistry / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated; D017433:Protein Structure, Secondary; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D017384:Sequence Deletion; D014982:Xenopus laevis
chemical_list: C496979:Kcna4 protein, rat; D051665:Kv1.4 Potassium Channel; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D006639:Histidine