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Wappl, E; Koschak, A; Poteser, M; Sinnegger, MJ; Walter, D; Eberhart, A; Groschner, K; Glossmann, H; Kraus, RL; Grabner, M; Striessnig, J.
Functional consequences of P/Q-type Ca2+ channel Cav2.1 missense mutations associated with episodic ataxia type 2 and progressive ataxia.
J Biol Chem. 2002; 277(9):6960-6966 Doi: 10.1074/jbc.M110948200 [OPEN ACCESS]
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Co-authors Med Uni Graz: Groschner Klaus; Poteser Michael
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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.
Find related publications in this database (using NLM MeSH Indexing): Amino Acid Sequence -; Animals -; Ataxia - genetics Ataxia - metabolism; Calcium Channels - genetics Calcium Channels - physiology; Calcium Channels, N-Type - genetics Calcium Channels, N-Type - physiology; Cell Line -; Cloning, Molecular -; DNA, Complementary - metabolism; Electrophysiology -; Humans -; Kinetics -; Molecular Sequence Data -; Mutation -; Mutation, Missense -; Oocytes - metabolism; Sequence Homology, Amino Acid -; Time Factors -; Xenopus -