Eur J Neurosci 2001 Sep 01;146:987-97. doi: 10.1046/j.0953-816x.2001.01728.x.

Distinct properties and differential beta subunit regulation of two C-terminal isoforms of the P/Q-type Ca(2+)-channel alpha(1A) subunit.

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Two C-terminal splice variants (BI-1 and BI-2, now termed Ca(v)2.1a and Ca(v)2.1b) of the neuronal voltage-gated P/Q-type Ca(2+) channel alpha(1A) pore-forming subunit have been cloned (Mori et al., 1991, Nature, 350, 398-402). BI-1 and BI-2 code for proteins of 2273 and 2424 amino acids, respectively, and differ only by their extreme carboxyl-termini sequences. Here, we show that, in Xenopus oocytes, the two isoforms direct the expression of channels with different properties. Electrophysiological analysis showed that BI-1 and BI-2 have peak Ba(2+) currents (I(Ba)) at a potential of +30 and +20 mV, respectively. The different C-terminal sequence (amino acids 2229-2273) of BI-1 caused a shift in steady-state inactivation by +10 mV and decreased the proportion of fast component of current inactivation twofold. Likewise, the biophysical changes in I(Ba) caused by coexpression of the beta(4) auxiliary subunit were substantially different in BI-1- and BI-2-containing channels in comparison to those induced by beta(3). Several of these differences in beta regulation were abolished by deleting the carboxyl-terminal splicing region. By creating a series of GST fusion proteins, we identified two locations in the C-terminal (Leu2090-Gly2229 for BI-1 and BI-2, and Arg2230-Pro2424 for BI-2 only) that determine the differential interaction of beta(4) with the distinct alpha(1A) isoforms. These interactions appear to favour the binding of beta(4) to the AID site, and also the plasma membrane expression of BI-2. These results demonstrate that the final segment of the C-terminal affects alpha(1A) channel gating, interaction and regulation with/by the beta subunits. The data will have several implications for the understanding of the biophysical effects of many channelopathies in which the carboxyl-termini of alpha(1A) and beta(4) are affected.

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Species referenced: Xenopus laevis
Genes referenced: tbx2