N‐type CaV2.2 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, CaV2.2e[37a], expressed in a subset of nociceptors and with limited expression in other parts of the nervous system. CaV2.2[e37a] arises from the mutually exclusive replacement of e37a for e37b in the C‐terminus of CaV2.2 mRNA. N‐type current densities in nociceptors that express a combination of CaV2.2e[37a] and CaV2.2e[37b] mRNAs are significantly larger compared to cells that express only CaV2.2e[37b]. Here we show that e37a supports increased expression of functional N‐type channels and an increase in channel open time as compared to CaV2.2 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 CaV2.2e[37a] and CaV2.2e[37b]. When activated, CaV2.2e[37a] channels remain open for longer and are expressed at higher density than CaV2.2e[37b] channels. These unique features of the CaV2.2e[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 CaV2.2 that regulates the overall activity of N‐type calcium channels in nociceptors.