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Alternative Splicing in the Voltage-Sensing Region of N-Type Ca_V2.2 Channels Modulates Channel Kinetics

¹Department of Neuroscience, Brown University, Providence, Rhode Island 02912; and ²Marine Biological Laboratory, Woods Hole, Massachusetts 02543

Submitted 14 January 2004; accepted in final form 14 June 2004

The Ca_V2.2 gene encodes the functional core of the N-type calcium channel. This gene has the potential to generate thousands of Ca_V2.2 splice isoforms with different properties. However, the functional significance of most sites of alternative splicing is not established. The IVS3-IVS4 region contains an alternative splice site that is conserved evolutionarily among Ca_V1 genes from Drosophila to human. In Ca_V2.2, inclusion of exon 31a in the IVS3-IVS4 region is restricted to the peripheral nervous system, and its inclusion slows the speed of channel activation. To investigate the effects of exon 31a in more detail, we generated four tsA201 cell lines stably expressing Ca_V2.2 splice isoforms. Coexpression of auxiliary Ca_V and Ca_V2 subunits was required to reconstitute currents with the kinetics of N-type channels from neurons. Channels including exon 31a activated and deactivated more slowly at all voltages. Current densities were high enough in the stable cell lines co-expressing Ca_V2 to resolve gating currents. The steady-state voltage dependence of charge movement was not consistently different between splice isoforms, but ON gating currents from the exon 31a-containing Ca_V2.2 isoform decayed with a slower time course, corresponding to slower movement of the charge sensor. Exon 31a-containing Ca_V2.2 is restricted to peripheral ganglia; and the slower gating kinetics of Ca_V2.2 splice isoforms containing exon 31a correlated reasonably well with the properties of native N-type currents in sympathetic neurons. Our results suggest that alternative splicing in the S3-S4 linker influences the kinetics but not the voltage dependence of N-type channel gating.

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