Calcium ion channels coordinate an astounding number of cellular functions. Surprisingly, only 10 Cavα1 subunit genes encode the structural cores of all voltage-gated calcium channels. What mechanisms exist to modify the structure of calcium channels and optimize their coupling to the rich spectrum of cellular functions? Growing evidence points to the contribution of post-translational alternative processing of calcium channel RNA as the main mechanism for expanding the functional potential of this important gene family. Alternative splicing of RNA is essential during neuronal development where fine adjustments in protein signaling promote and inhibit cell-cell interactions and underlie axonal guidance. However, attributing a specific functional role to an individual splice isoform or splice site has been difficult. In this regard, studies of ion channels are advantageous because their function can be monitored with precision, allowing even subtle changes in channel activity to be detected. Such studies are especially insightful when coupled with information about isoform expression patterns and cellular localization.In this paper we focus on two sites of alternative splicing in the N-type calcium channel Cav2.2 gene. We first describe cassette exon 18a that encodes a 21 amino acid segment in the II-III intracellular loop region of Cav2.2. Here we show that e18a is up-regulated in the nervous system during development. We discuss these new data in light of our previous reports showing that e18a protects the N-type channel from cumulative inactivation. Second, we discuss our published data on exons e37a and e37b, which encode 32 amino acids in the intracellular C-terminus of Cav2.2. These exons are expressed in a mutually exclusive manner. Exon e37a-containing Cav2.2 mRNAs and their resultant channels express at higher density in dorsal root ganglia and, as we showed recently, e37a increases N-type channel sensitivity to G protein-mediated inhibition, as compared to generic e37b-containing N-type channels.
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