The neuronal splicing factor Nova controls alternative splicing in N-type and P-type CaV2 calcium channels

Many cellular processes are involved in optimizing protein function for specific neuronal tasks; here we focus on alternative pre-mRNA splicing. Alternative pre-mRNA splicing gives cells the capacity to modify and selectively re-balance their existing pool of transcripts in a coordinated way across multiple mRNAs, thereby effecting relatively rapid and relatively stable changes in protein activity. Here we report on and discuss the coordinated regulation of two sites of alternative splicing, e24a and e31a, in P-type Ca(V)2.1 and N-type Ca(V)2.2 channels. These two exons encode 4 and 2 amino acids, respectively, in the extracellular linker regions between transmembrane spanning segments S3 and S4 in domains III and IV of each Ca(V)2 subunit. Recent genome-wide screens of splicing factor-RNA binding events by Darnell and colleagues show that Nova-2 promotes inclusion of e24a in Ca(V)2.2 mRNAs in brain. We review these studies and show that a homologous e24a is present in the Ca(V)2.1 gene, Cacna1a, and that it is expressed in different regions of the nervous system. Nova-2 enhances inclusion of e24a but represses e31a inclusion in Ca(V)2.1 and Ca(V)2.2 mRNAs in brain. It is likely that coordinated alternative pre-mRNA splicing across related Ca(V)2 genes by common splicing factors allows neurons to orchestrate changes in synaptic protein function while maintaining a balanced and functioning system.