Abstract
L-type calcium channels composed of a pore-forming Cav1.2 (α1C) subunit and auxiliary α2δ and β-subunits are important for cardiovascular and neuronal function. Cav1.2 and β-subunits are subject to alternative splicing, which affects their biophysical and pharmacological properties. Here we describe an example of reciprocal modulation of such splice variants.Kanevsky and Dascal (J Gen Physiol. 2006;128:15-36) demonstrated that the modulation of Cav1.2 by a β2b-subunit depends on the Cav1.2 N-terminus (NT) and its natural and artificial variants. On the other hand, studies on the structure-activity relationship of β2-subunit NT splice variants yielded conflicting results (Takahashi et al., Biophys J 2003; 84:3007-21, Herzig et al., FASEB J 2007;21:1527-38, Link et al., J Biol Chem 2009;284:30129-37), possibly due to the different Cav1.2 subunits chosen.Here we examine the putative interaction between the two NT by coexpressing two variants of Cav1.2 (short NT and long NT) with three splice variants of β2-subunit β2a, β2b and β2d), which differ in size and composition of their NT. All possible combinations of murine constructs (including α2δ-1) were transiently expressed in HEK293 cells. Whole-cell and single-channel currents were recorded.Whole-cell currents of β2a-containing channel complexes display slower time-dependent inactivation compared with β2b and β2d, irrespective of the Cav1.2 NT. In contrast, whole-cell current density is higher with β2a (compared to β2b and β2d), but only when co-expressed with long NT Cav1.2. At the single-channel level, this is reflected by an elevated open probability and availability for the β2a-containing complex when co-expressed with long NT Cav1.2, but not with short NT Cav1.2. The respective NT of Cav1.2 and its β2-subunit can interact in a biophysically important manner. This mechanism may contribute to functional fine-tuning of channel complexes by alternative splicing.
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