Please use this identifier to cite or link to this item: https://doi.org/10.1016/j.bpj.2018.03.029
Title: Alternative Splicing at N Terminus and Domain I Modulates Ca(v)1.2 Inactivation and Surface Expression
Authors: Bartels, Peter
Yu, Dejie 
Huang, Hua 
Hu, Zhenyu 
Herzig, Stefan
Soong, Tuck Wah 
Keywords: Science & Technology
Life Sciences & Biomedicine
Biophysics
GATED CALCIUM-CHANNEL
SMOOTH-MUSCLE-CELLS
CA2+ CHANNEL
MOLECULAR DETERMINANTS
ALPHA(1C) SUBUNIT
AUXILIARY SUBUNITS
BETA-SUBUNITS
EXONS 40-42
CALMODULIN
HEART
Issue Date: 8-May-2018
Publisher: CELL PRESS
Citation: Bartels, 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
Abstract: The 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.
Source Title: BIOPHYSICAL JOURNAL
URI: https://scholarbank.nus.edu.sg/handle/10635/218660
ISSN: 0006-3495
1542-0086
DOI: 10.1016/j.bpj.2018.03.029
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