Alternative Splicing Matters: N-Type Calcium Channels in Nociceptors

Abstract

How many different calcium channels does it take to make a nervous system? The answer: more than any of us predicted. In 1975 Hagiwara and colleagues published the first evidence that functionally different calcium channels are expressed in cells 1. By 1999, the calcium channel family could boast ten members, each member defined by a unique set of attributes to support their cellular functions and by unique amino acid sequences 2. Although nine of these genes are expressed in the nervous system, that number still seemed insufficient to support the wide spectrum of neuronal functions controlled by voltage-gated calcium channels. This discrepancy is probably explained by alternative pre-messenger RNA splicing which substantially expands the number of protein activities available from a limited number of genes. Like many other ion channel genes, each CaVa1 gene has the capacity to generate perhaps thousands of unique splice isoforms with unique functional properties 3. The high level of conservation among alternatively spliced exons in CaV2.2 genes of different species and in some cases closely related genes implies biological importance. A number of CaVa1 isoforms have been identified from neural tissue but until recently we lacked direct evidence linking a specific splice site in a calcium channel gene to a specific function in an identified neuron population.