Alternative splicing in the C‐terminus of Ca V 2.2 controls expression and gating of N‐type calcium channels

N‐type Ca V 2.2 calcium channels localize to presynaptic nerve terminals of nociceptors where they control neurotransmitter release. Nociceptive neurons express a unique set of ion channels and receptors important for optimizing their role in transmission of noxious stimuli. Included among these is a structurally and functionally distinct N‐type calcium channel splice isoform, Ca V 2.2e[37a], expressed in a subset of nociceptors and with limited expression in other parts of the nervous system. Ca V 2.2[e37a] arises from the mutually exclusive replacement of e37a for e37b in the C‐terminus of Ca V 2.2 mRNA. N‐type current densities in nociceptors that express a combination of Ca V 2.2e[37a] and Ca V 2.2e[37b] mRNAs are significantly larger compared to cells that express only Ca V 2.2e[37b]. Here we show that e37a supports increased expression of functional N‐type channels and an increase in channel open time as compared to Ca V 2.2 channels that contain e37b. To understand how e37a affects N‐type currents we compared macroscopic and single‐channel ionic currents as well as gating currents in tsA201 cells expressing Ca V 2.2e[37a] and Ca V 2.2e[37b]. When activated, Ca V 2.2e[37a] channels remain open for longer and are expressed at higher density than Ca V 2.2e[37b] channels. These unique features of the Ca V 2.2e[37a] isoform combine to augment substantially the amount of calcium that enters cells in response to action potentials. Our studies of the e37a/e37b splice site reveal a multifunctional domain in the C‐terminus of Ca V 2.2 that regulates the overall activity of N‐type calcium channels in nociceptors.