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Dominant-negative suppression of Cav2.1 currents by alpha(1)2.1 truncations requires the conserved interaction domain for beta subunits.

ABSTRACT: Episodic ataxia type 2 (EA2) is an autosomal dominant disorder arising from CACNA1A mutations, which commonly predict heterozygous expression of Ca(v)2.1 calcium channels with truncated alpha(1)2.1 pore subunits. We hypothesized that alpha(1)2.1 truncations in EA2 exert dominant-negative effects on the function of wild-type subunits. Wild-type and truncated alpha(1)2.1 subunits with fluorescent protein tags were transiently co-expressed in cells stably expressing Ca(v) auxiliary beta subunits, which facilitate alpha1 subunit functional expression through high-affinity interactions with the alpha interaction domain (AID). Co-expression of wild-type subunits with truncations often resulted in severely reduced whole-cell currents compared to expression of wild-type subunits alone. Cellular image analyses revealed that current suppression was not due to reduced wild-type expression levels. Instead, the current suppression depended on truncations terminating distal to the AID. Moreover, only AID-bearing alpha(1)2.1 proteins co-immunoprecipitated with Ca(v) beta subunits. These results indicate that Ca(v) beta subunits may play a prominent role in EA2 disease pathogenesis.

SUBMITTER: Raike RS

PROVIDER: S-EPMC3236250 | biostudies-literature | 2007 Feb

REPOSITORIES: biostudies-literature

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Dominant-negative suppression of Cav2.1 currents by alpha(1)2.1 truncations requires the conserved interaction domain for beta subunits.

Raike Robert S RS Kordasiewicz Holly B HB Thompson Randall M RM Gomez Christopher M CM

Molecular and cellular neurosciences 20061211 2

Episodic ataxia type 2 (EA2) is an autosomal dominant disorder arising from CACNA1A mutations, which commonly predict heterozygous expression of Ca(v)2.1 calcium channels with truncated alpha(1)2.1 pore subunits. We hypothesized that alpha(1)2.1 truncations in EA2 exert dominant-negative effects on the function of wild-type subunits. Wild-type and truncated alpha(1)2.1 subunits with fluorescent protein tags were transiently co-expressed in cells stably expressing Ca(v) auxiliary beta subunits, w ...[more]

PMID: 17161621

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Dataset Information

Dominant-negative suppression of Cav2.1 currents by alpha(1)2.1 truncations requires the conserved interaction domain for beta subunits.

Publications

Dominant-negative suppression of Cav2.1 currents by alpha(1)2.1 truncations requires the conserved interaction domain for beta subunits.

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