Novel approaches to examine the regulation of voltage-gated calcium channels in the heart

Author(s): John P. Morrow, Steven O. Marx

Journal Name: Current Molecular Pharmacology

Volume 8 , Issue 1 , 2015

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Abstract:

The cardiac L-type Ca2+ channel plays a key role in cardiac excitation-contraction coupling, action potential duration, and gene expression. Abnormalities in CaV1.2 function, including increased long-opening-mode gating and blunted adrenergic responsiveness, are associated with heart failure and hypertrophy. The increased activation of CaV1.2, in turn, triggers Ca2+ -responsive signaling pathways, which contribute to the pathogenesis of heart failure and hypertrophy. CaV1.2 in heart is associated with large supramolecular complexes that impact on channel trafficking, localization, turnover, and function. Much of the prevailing dogma relating to mechanisms underlying CaV1.2 trafficking and modulation is derived from studies using recombinant channels reconstituted in heterologous expression systems. However, recent results using knock-in mice indicate that several long-standing “facts” about CaV1.2 regulation derived from heterologous expression studies are not replicated in native heart, emphasizing the critical need for mechanistic studies in the context of actual cardiomyocytes. In this review, we discuss the use of the use of knockin and knockout mice as well as new tools, including doxycycline-induced expression of informative α1C mutants within cardiomyocytes to probe adrenergic regulation of CaV1.2.

Keywords: Calcium channel, heart, phosphorylation, PKA, transgenic.

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Article Details

VOLUME: 8
ISSUE: 1
Year: 2015
Page: [61 - 68]
Pages: 8
DOI: 10.2174/1874467208666150507094022

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