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- W2029365961 abstract "Background. The LTCC distal C-terminus (DCT) is proteolytically cleaved, and re-associates with the LTCC complex to regulate calcium channel function. DCT reduces LTCC barium current (IBa,L) in reconstituted channel complexes and mediates the fight or flight response in DCT knockout mice; yet the contribution of DCT to ICa,L in native systems is unexplored. This study examines the beat-to beat contribution of DCT to LTCC calcium homeostasis in native cardiomyocytes. Methods. We measured LTCC current with DCT co-expressed in cardiomyocytes. We also heterologously co-expressed DCT and CaV1.2 constructs with a stop corresponding to the predicted proteolytic cleavage site, Cav1.2Δ1801, and a shorter deletion corresponding to well-studied construct, Cav1.2Δ1733 along with CaVβ2 subunits. Results. DCT was found to inhibit IBa,L, but not ICa,L in cardiomyocytes. DCT blocked IBa,L carried by both Cav1.2Δ1801 and Cav1.2Δ1733 in HEK cells. However, DCT inhibited ICa,L carried by Cav1.2Δ1801 but not Cav1.2Δ1733 channels. As CaM and DCT have adjoining interaction sites on CaV1.2, we tested if exogenous CaM (CaMex) interferes with DCT current inhibition in cardiomyocytes and HEK systems. CaMex relieved DCT block in both systems and both channel variants. Addition of CaM1234 did not relieve DCT current inhibition or have an additive effect. DCT did not alter voltage dependence, or activation kinetics. The selective block of IBa,L suggested that DCT activity may be relieved under conditions of elevated Ca. Conclusions. DCT blockade of LTCC is apparent only when Ca is not the charge carrier. Therefore, our data motivates the new hypothesis that DCT is a native reverse use-dependent inhibitor of LTCC current." @default.
- W2029365961 created "2016-06-24" @default.
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- W2029365961 date "2012-01-01" @default.
- W2029365961 modified "2023-09-26" @default.
- W2029365961 title "The Cardiac L-Type Calcium Channel Distal Carboxyl Terminus is a Reverse use Dependent Inhibitor of Ca Current in Cardiomyocytes" @default.
- W2029365961 doi "https://doi.org/10.1016/j.bpj.2011.11.702" @default.
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