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Functional characterization of CaValpha2delta mutations associated with sudden cardiac death.

Authors: Bourdin, B  Shakeri, B  Tetreault, MP  Sauve, R  Lesage, S  Parent, L 
Citation: Bourdin B, etal., J Biol Chem. 2015 Jan 30;290(5):2854-69. doi: 10.1074/jbc.M114.597930. Epub 2014 Dec 19.
Pubmed: (View Article at PubMed) PMID:25527503
DOI: Full-text: DOI:10.1074/jbc.M114.597930

L-type Ca(2+) channels play a critical role in cardiac rhythmicity. These ion channels are oligomeric complexes formed by the pore-forming CaValpha1 with the auxiliary CaVbeta and CaValpha2delta subunits. CaValpha2delta increases the peak current density and improves the voltage-dependent activation gating of CaV1.2 channels without increasing the surface expression of the CaValpha1 subunit. The functional impact of genetic variants of CACNA2D1 (the gene encoding for CaValpha2delta), associated with shorter repolarization QT intervals (the time interval between the Q and the T waves on the cardiac electrocardiogram), was investigated after recombinant expression of the full complement of L-type CaV1.2 subunits in human embryonic kidney 293 cells. By performing side-by-side high resolution flow cytometry assays and whole-cell patch clamp recordings, we revealed that the surface density of the CaValpha2delta wild-type protein correlates with the peak current density. Furthermore, the cell surface density of CaValpha2delta mutants S755T, Q917H, and S956T was not significantly different from the cell surface density of the CaValpha2delta wild-type protein expressed under the same conditions. In contrast, the cell surface expression of CaValpha2delta D550Y, CaValpha2delta S709N, and the double mutant D550Y/Q917H was reduced, respectively, by approximately 30-33% for the single mutants and by 60% for the latter. The cell surface density of D550Y/Q917H was more significantly impaired than protein stability, suggesting that surface trafficking of CaValpha2delta was disrupted by the double mutation. Co-expression with D550Y/Q917H significantly decreased CaV1.2 currents as compared with results obtained with CaValpha2delta wild type. It is concluded that D550Y/Q917H reduced inward Ca(2+) currents through a defect in the cell surface trafficking of CaValpha2delta. Altogether, our results provide novel insight in the molecular mechanism underlying the modulation of CaV1.2 currents by CaValpha2delta.


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RGD Object Information
RGD ID: 11059598
Created: 2016-04-16
Species: All species
Last Modified: 2016-04-16
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.