Does the voltage‐gated calcium channel α2δ‐1 subunit play a dual function in skeletal muscle?

Abstract

The dihydropyridine receptor (DHPR), a high voltage-activated calcium (Ca2+) channel, represents a key element in the excitation–contraction (EC) coupling machinery of muscle cells. In skeletal muscle, the DHPR fulfils two known functions: (i) it controls the ryanodine receptor activity, which makes it commonly referred to as the voltage-sensor for EC coupling and (ii) it supports an L-type voltage-activated Ca2+ current. The DHPR is a macromolecular complex composed of the Cav1.1 pore-forming subunit, surrounded by β1a, γ1 and α2δ-1 auxiliary subunits. Whereas knock-out animals have clearly demonstrated the essential role of Cav1.1 and β1a subunits in EC coupling and in the control of the Ca2+ conductance, the functional importance of α2δ-1 in skeletal muscle remains largely elusive, despite the lethal phenotype of α2δ-1-null embryos. Interestingly, down-regulation of the α2δ-1 protein in the BC3H1 muscle cell line with siRNA only resulted in acceleration of Ca2+ current activation kinetics with no effect on both EC coupling and Cav1.1 trafficking (Obermair et al. 2005). However, it is hard to understand how alteration of Ca2+ current kinetics could be the cause of the lethal phenotype observed in α2δ-1-null mice embryos; instead α2δ-1 is most likely to be involved in other cell functions independent of the DHPR activity. Previous observations suggested such a function: (i) α2δ-1 appears early during muscle development, at a period when the Cav1.1 subunit is not yet expressed, and (ii) sequence analysis of α2δ-1 revealed the presence of consensus domains, known to be involved in cell adhesion and protein–protein interactions (see Fig. 1 for structural organization of the α2δ-1 subunit). In a recent issue of The Journal of Physiology, Garcia et al. raised the possibility that α2δ-1 could mediate the interaction of muscle cells with the extracellular matrix (Garcia et al. 2008). Using immunohistochemistry and a siRNA knock-down strategy, the authors provided new insights into the functional involvement of α2δ-1 in skeletal muscle cells.