title: Functional consequences of P/Q-type Ca2+ channel Cav2.1 missense mutations associated with episodic ataxia type 2 and progressive ataxia.
abstract: We have investigated the functional consequences of three P/Q-type Ca(2+) channel alpha1A (Ca(v)2.1alpha(1)) subunit mutations associated with different forms of ataxia (episodic ataxia type 2 (EA-2), R1279Stop, AY1593/1594D; progressive ataxia (PA), G293R). Mutations were introduced into human alpha1A cDNA and heterologously expressed in Xenopus oocytes or tsA-201 cells (with alpha(2)delta and beta1a) for electrophysiological and biochemical analysis. G293R reduced current density in both expression systems without changing single channel conductance. R1279Stop and AY1593/1594D protein were expressed in tsA-201 cells but failed to yield inward barium currents (I(Ba)). However, AY1593/1594D mediated I(Ba) when expressed in oocytes. G293R and AY1593/1594D shifted the current-voltage relationship to more positive potentials and enhanced inactivation during depolarizing pulses (3 s) and pulse trains (100 ms, 1 Hz). Mutation AY1593/1594D also slowed recovery from inactivation. Single channel recordings revealed a change in fast channel gating for G293R evident as a decrease in the mean open time. Our data support the hypothesis that a pronounced loss of P/Q-type Ca(2+) channel function underlies the pathophysiology of EA-2 and PA. In contrast to other EA-2 mutations, AY1593/1594D and G293R form at least partially functional channels.
authors.affiliation: Institut für Biochemische Pharmakologie, Abteilung Pharmakologie und Toxikologie, Institut für Pharmazie, Universität Innsbruck, Peter-Mayrstrasse 1, A-6020 Innsbruck, Austria.
authors.forename: Edwin
authors.initials: E
authors.lastname: Wappl
authors.forename: Alexandra
authors.initials: A
authors.lastname: Koschak
authors.forename: Michael
authors.initials: M
authors.lastname: Poteser
authors.forename: Martina J
authors.initials: MJ
authors.lastname: Sinnegger
authors.forename: Doris
authors.initials: D
authors.lastname: Walter
authors.forename: Andreas
authors.initials: A
authors.lastname: Eberhart
authors.forename: Klaus
authors.initials: K
authors.lastname: Groschner
authors.forename: Hartmut
authors.initials: H
authors.lastname: Glossmann
authors.forename: Richard L
authors.initials: RL
authors.lastname: Kraus
authors.forename: Manfred
authors.initials: M
authors.lastname: Grabner
authors.forename: Jörg
authors.initials: J
authors.lastname: Striessnig
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001259:Ataxia / Q000235:genetics* / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics* / Q000502:physiology*; D020864:Calcium Channels, N-Type / Q000235:genetics* / Q000502:physiology*; D002460:Cell Line; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000378:metabolism; D004594:Electrophysiology; D006801:Humans; D007700:Kinetics; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D009865:Oocytes / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013997:Time Factors; D014981:Xenopus
chemical_list: D015220:Calcium Channels; D020864:Calcium Channels, N-Type; D018076:DNA, Complementary