Please use this identifier to cite or link to this item: https://doi.org/10.1016/j.bpj.2018.03.029
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dc.titleAlternative Splicing at N Terminus and Domain I Modulates Ca(v)1.2 Inactivation and Surface Expression
dc.contributor.authorBartels, Peter
dc.contributor.authorYu, Dejie
dc.contributor.authorHuang, Hua
dc.contributor.authorHu, Zhenyu
dc.contributor.authorHerzig, Stefan
dc.contributor.authorSoong, Tuck Wah
dc.date.accessioned2022-04-08T01:30:57Z
dc.date.available2022-04-08T01:30:57Z
dc.date.issued2018-05-08
dc.identifier.citationBartels, Peter, Yu, Dejie, Huang, Hua, Hu, Zhenyu, Herzig, Stefan, Soong, Tuck Wah (2018-05-08). Alternative Splicing at N Terminus and Domain I Modulates Ca(v)1.2 Inactivation and Surface Expression. BIOPHYSICAL JOURNAL 114 (9) : 2095-2106. ScholarBank@NUS Repository. https://doi.org/10.1016/j.bpj.2018.03.029
dc.identifier.issn0006-3495
dc.identifier.issn1542-0086
dc.identifier.urihttps://scholarbank.nus.edu.sg/handle/10635/218660
dc.description.abstractThe CaV1.2 L-type calcium channel is a key conduit for Ca2+ influx to initiate excitation-contraction coupling for contraction of the heart and vasoconstriction of the arteries and for altering membrane excitability in neurons. Its α1C pore-forming subunit is known to undergo extensive alternative splicing to produce many CaV1.2 isoforms that differ in their electrophysiological and pharmacological properties. Here, we examined the structure-function relationship of human CaV1.2 with respect to the inclusion or exclusion of mutually exclusive exons of the N-terminus exons 1/1a and IS6 segment exons 8/8a. These exons showed tissue selectivity in their expression patterns: heart variant 1a/8a, one smooth-muscle variant 1/8, and a brain isoform 1/8a. Overall, the 1/8a, when coexpressed with CaVβ2a, displayed a significant and distinct shift in voltage-dependent activation and inactivation and inactivation kinetics as compared to the other three splice variants. Further analysis showed a clear additive effect of the hyperpolarization shift in V1/2inact of CaV1.2 channels containing exon 1 in combination with 8a. However, this additive effect was less distinct for V1/2act. However, the measured effects were β-subunit-dependent when comparing CaVβ2a with CaVβ3 coexpression. Notably, calcium-dependent inactivation mediated by local Ca2+-sensing via the N-lobe of calmodulin was significantly enhanced in exon-1-containing CaV1.2 as compared to exon-1a-containing CaV1.2 channels. At the cellular level, the current densities of the 1/8a or 1/8 variants were significantly larger than the 1a/8a and 1a/8 variants when coexpressed either with CaVβ2a or CaVβ3 subunit. This finding correlated well with a higher channel surface expression for the exon 1-CaV1.2 isoform that we quantified by protein surface-expression levels or by gating currents. Our data also provided a deeper molecular understanding of the altered biophysical properties of alternatively spliced human CaV1.2 channels by directly comparing unitary single-channel events with macroscopic whole-cell currents.
dc.language.isoen
dc.publisherCELL PRESS
dc.sourceElements
dc.subjectScience & Technology
dc.subjectLife Sciences & Biomedicine
dc.subjectBiophysics
dc.subjectGATED CALCIUM-CHANNEL
dc.subjectSMOOTH-MUSCLE-CELLS
dc.subjectCA2+ CHANNEL
dc.subjectMOLECULAR DETERMINANTS
dc.subjectALPHA(1C) SUBUNIT
dc.subjectAUXILIARY SUBUNITS
dc.subjectBETA-SUBUNITS
dc.subjectEXONS 40-42
dc.subjectCALMODULIN
dc.subjectHEART
dc.typeArticle
dc.date.updated2022-04-08T00:11:13Z
dc.contributor.departmentDEPT OF PHYSIOLOGY
dc.contributor.departmentPHYSIOLOGY
dc.description.doi10.1016/j.bpj.2018.03.029
dc.description.sourcetitleBIOPHYSICAL JOURNAL
dc.description.volume114
dc.description.issue9
dc.description.page2095-2106
dc.published.statePublished
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