Molecular characterization of a two‐domain form of the neuronal voltage‐gated P/Q‐type calcium channel α12.1 subunit

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Abstract
We characterized the neuronal two‐domain (95kD‐α12.1) form of the α12.1 subunit of the voltage‐gated calcium channels using genetic and molecular analysis. The 95kD‐α12.1 is absent in neuronal preparations from CACNA1A null mouse demonstrating that α12.1 and 95kD‐α12.1 arise from the same gene. A recombinant two‐domain form (α1AI‐II) of α12.1 associates with the β subunit and is trafficked to the plasma membrane. Translocation of the α1AI‐II to the plasma membrane requires association with the β subunit, since a mutation in the α1AI‐II that inhibits β subunit association reduces membrane trafficking. Though the α1AI‐II protein does not conduct any voltage‐gated currents, we have previously shown that it generates a high density of non‐linear charge movements [Ahern et al., Proc. Natl. Acad. Sci. USA 98 (2001) 6935–6940]. In this study, we demonstrate that co‐expression of the α1AI‐II significantly reduces the current amplitude of α12.1/β1a/α2δ channels, via competition for the β subunit. Taken together, our results demonstrate a dual functional role for the α1AI‐II protein, both as a voltage sensor and modulator of P/Q‐type currents in recombinant systems. These studies suggest an in vivo role for the 95kD‐α12.1 in altering synaptic activity via protein–protein interactions and/or regulation of P/Q‐type currents.

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