Divergent biophysical properties, gating mechanisms, and possible functions of the two skeletal muscle Ca(V)1.1 calcium channel splice variants

Abstract

Voltage-gated calcium channels are multi-subunit protein complexes that specifically allow calcium ions to enter the cell in response to membrane depolarization. But, for many years it seemed that the skeletal muscle calcium channel Ca(V)1.1 is the exception. The classical splice variant Ca(V)1.1a activates slowly, has a very small current amplitude and poor voltage sensitivity. In fact adult muscle fibers work perfectly well even in the absence of calcium influx. Recently a new splice variant of the skeletal muscle calcium channel Ca(V)1.1e has been characterized. The lack of the 19 amino acid exon 29 in this splice variant results in a rapidly activating calcium channel with high current amplitude and good voltage sensitivity. Ca(V)1.1e is the dominant channel in embryonic muscle, where the expression of this high calcium-conducting Ca(V)1.1 isoform readily explains developmental processes depending on L-type calcium currents. Moreover, the availability of these two structurally similar but functionally distinct channel variants facilitates the analysis of the molecular mechanisms underlying the unique current properties of the classical Ca(V)1.1a channel.

Fig. 1

Structure of the skeletal muscle calcium channel α_1S subunit. a Predicted transmembrane topology of Ca_V1.1 α_1S subunit. The regions of the cytoplasmic loops interacting with the β subunit and the RyR1 are emphasized in gray, while the location of exon 29, which is missing in the Ca_V1.1e isoform is highlighted in green. b Sequence alignment of the extracellular S3–S4 linkers together with the S4 transmembrane segment from repeats one to four of the skeletal muscle calcium channel. The amino acid sequence encoded by the exon 29 in IVS3–S4 linker is highlighted in green, while red letters emphasize the positively charged residues responsible for the detection of the membrane depolarization. (Color figure online)