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- W2071769488 abstract "L-type Ca 2+ currents determine the shape of cardiac action potentials (AP) and the magnitude of the myoplasmic Ca 2+ signal, which regulates the contraction force. The auxiliary Ca 2+ channel subunits α 2 δ-1 and β 2 are important regulators of membrane expression and current properties of the cardiac Ca 2+ channel (Ca V 1.2). However, their role in cardiac excitation–contraction coupling is still elusive. Here we addressed this question by combining siRNA knockdown of the α 2 δ-1 subunit in a muscle expression system with simulation of APs and Ca 2+ transients by using a quantitative computer model of ventricular myocytes. Reconstitution of dysgenic muscle cells with Ca V 1.2 (GFP-α 1C ) recapitulates key properties of cardiac excitation–contraction coupling. Concomitant depletion of the α 2 δ-1 subunit did not perturb membrane expression or targeting of the pore-forming GFP-α 1C subunit into junctions between the outer membrane and the sarcoplasmic reticulum. However, α 2 δ-1 depletion shifted the voltage dependence of Ca 2+ current activation by 9 mV to more positive potentials, and it slowed down activation and inactivation kinetics approximately 2-fold. Computer modeling revealed that the altered voltage dependence and current kinetics exert opposing effects on the function of ventricular myocytes that in total cause a 60% prolongation of the AP and a 2-fold increase of the myoplasmic Ca 2+ concentration during each contraction. Thus, the Ca 2+ channel α 2 δ-1 subunit is not essential for normal Ca 2+ channel targeting in muscle but is a key determinant of normal excitation and contraction of cardiac muscle cells, and a reduction of α 2 δ-1 function is predicted to severely perturb normal heart function." @default.
- W2071769488 created "2016-06-24" @default.
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- W2071769488 date "2007-06-26" @default.
- W2071769488 modified "2023-10-02" @default.
- W2071769488 title "Computer modeling of siRNA knockdown effects indicates an essential role of the Ca <sup>2+</sup> channel α <sub>2</sub> δ-1 subunit in cardiac excitation–contraction coupling" @default.
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- W2071769488 doi "https://doi.org/10.1073/pnas.0700577104" @default.
- W2071769488 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/1904133" @default.
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