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The Interplay Between Splicing of Two Exon Combinations Differentially Affects Membrane Targeting and Function of Human CaV2.2

Dahimene, Shehrazade; Page, Karen M; Nieto-Rostro, Manuela; Pratt, Wendy S; Dolphin, Annette C; (2023) The Interplay Between Splicing of Two Exon Combinations Differentially Affects Membrane Targeting and Function of Human CaV2.2. Function , 5 (1) , Article zqad060. 10.1093/function/zqad060. Green open access

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Abstract

N-type calcium channels (CaV2.2) are predominantly localized in presynaptic terminals, and are particularly important for pain transmission in the spinal cord. Furthermore, they have multiple isoforms, conferred by alternatively spliced or cassette exons, which are differentially expressed. Here, we have examined alternatively spliced exon47 variants that encode a long or short C-terminus in human CaV2.2. In the Ensembl database, all short exon47-containing transcripts were associated with the absence of exon18a, therefore, we also examined the effect of inclusion or absence of exon18a, combinatorially with the exon47 splice variants. We found that long exon47, only in the additional presence of exon18a, results in CaV2.2 currents that have a 3.6-fold greater maximum conductance than the other three combinations. In contrast, cell-surface expression of CaV2.2 in both tsA-201 cells and hippocampal neurons is increased ∼4-fold by long exon47, relative to short exon47, in either the presence or the absence of exon18a. This surprising discrepancy between trafficking and function indicates that cell-surface expression is enhanced by long exon47, independently of exon18a. However, in the presence of long exon47, exon18a mediates an additional permissive effect on CaV2.2 gating. We also investigated the single-nucleotide polymorphism in exon47 that has been linked to schizophrenia and Parkinson's disease, which we found is only non-synonymous in the short exon47 C-terminal isoform, resulting in two minor alleles. This study highlights the importance of investigating the combinatorial effects of exon inclusion, rather than each in isolation, in order to increase our understanding of calcium channel function.

Type: Article
Title: The Interplay Between Splicing of Two Exon Combinations Differentially Affects Membrane Targeting and Function of Human CaV2.2
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1093/function/zqad060
Publisher version: https://doi.org/10.1093/function/zqad060
Language: English
Additional information: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third-party material in this article are included in the Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Keywords: Calcium, current, electrophysiology, ion channel, patch clamp, single-nucleotide polymorphism, splice variant, trafficking, Humans, Neurons, RNA Splicing, Calcium Channels, N-Type, Protein Isoforms, Exons
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: https://discovery.ucl.ac.uk/id/eprint/10183610
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