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Alternative splicing in the C‐terminus of Ca V 2.2 controls expression and gating of N‐type calcium channels
Author(s) -
Castiglioni Andrew J.,
Raingo Jesica,
Lipscombe Diane
Publication year - 2006
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2006.115030
Subject(s) - gating , gene isoform , chemistry , t type calcium channel , alternative splicing , voltage dependent calcium channel , nociceptor , microbiology and biotechnology , neuroscience , calcium , biophysics , nociception , receptor , biology , biochemistry , gene , organic chemistry
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.