Molecular Diversity of the Calcium Channel α₂δ Subunit

TLDR

Sequence database searches identified two novel alpha2δ genes encoding proteins with the essential properties of calcium channel subunits. Alpha2δ‑2 and α2δ‑3, sharing 55.6 % and 30.3 % identity with α2δ‑1, contain characteristic glycosylation sites, cysteines, and hydropathic profiles that confirm them as functional calcium‑channel subunits; co‑expression with α1C or α1E shifts voltage dependence hyperpolarizing and accelerates inactivation, with α2δ‑3 effects on α1C indistinguishable from α2δ‑1, while α2δ‑3 is brain‑restricted and α2δ‑2 is broadly expressed, and in situ hybridization shows α2δ‑1 and α2δ‑3 in hippocampus, cerebellum, cortex, olfactory bulb, and caudate putamen.

Abstract

Sequence database searches with the alpha2delta subunit as probe led to the identification of two new genes encoding proteins with the essential properties of this calcium channel subunit. Primary structure comparisons revealed that the novel alpha2delta-2 and alpha2delta-3 subunits share 55.6 and 30.3% identity with the alpha2delta-1 subunit, respectively. The number of putative glycosylation sites and cysteine residues, hydropathicity profiles, and electrophysiological character of the alpha2delta-3 subunit indicates that these proteins are functional calcium channel subunits. Coexpression of alpha2delta-3 with alpha1C and cardiac beta2a or alpha1E and beta3 subunits shifted the voltage dependence of channel activation and inactivation in a hyperpolarizing direction and accelerated the kinetics of current inactivation. The kinetics of current activation were altered only when alpha2delta-1 or alpha2delta-3 was expressed with alpha1C. The effects of alpha2delta-3 on alpha1C but not alpha1E are indistinguishable from the effects of alpha2delta-1. Using Northern blot analysis, it was shown that alpha2delta-3 is expressed exclusively in brain, whereas alpha2delta-2 is found in several tissues. In situ hybridization of mouse brain sections showed mRNA expression of alpha2delta-1 and alpha2delta-3 in the hippocampus, cerebellum, and cortex, with alpha2delta-1 strongly detected in the olfactory bulb and alpha2delta-3 in the caudate putamen.