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. Proper targeting of CaV1.2 to distinct surface sites, and hormonal regulation of their activity, is vital for normal cardiac physiology. 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. Unfortunately, however, at least some of the most critical questions regarding trafficking and regulation by ?-adrenergic agonists in cardiomyocytes cannot be assessed using heterologous expression, likely because the unique intracellular environment of cardiomyocytes is not reproduced elsewhere. In the previous funding period, we developed and implemented innovative methods to probe determinants underlying CaV1.2 trafficking and ?- adrenergic regulation directly in cardiomyocytes. Using this approach, our findings that ?-less ?1C in adult cardiomyocytes generate CaV1.2 channels with normal basal activity that are not regulated by PKA provide the first opportunity to probe the relative contribution of this modulation to sympathetic regulation in the fight or flight response. We propose three Aims that build on our previous findings, and designed to deepen mechanistic understanding of CaV1.2 regulation in heart: (1) Determine the role of CaV? binding to ?1C in regulating cardiac contractility in vivo; (2) To determine the mechanism(s) by which ? subunits enable ?- adrenergic regulation of CaV1.2. (3) To elucidate the mechanisms of ?-dependent and ?-independent CaV1.2 channel trafficking. The three Aims, which should provide key new understandings concerning the regulation of Ca2+ influx in cardiomyocytes, are highly relevant towards understanding cardiac pathologies and the molecular mechanisms responsible for cardiac excitation-contraction coupling and adrenergic modulation of the cardiac Ca2+ channel.

Public Health Relevance

Abnormal trafficking and hormonal-modulation of CaV1.2 channels is associated with cardiovascular diseases such as heart failure, cardiac hypertrophy and arrhythmias. Our proposal focuses on understanding molecular mechanisms of CaV1.2 trafficking and regulation in heart cells. The studies will provide deepened insights into the molecular basis of cardiovascular diseases and could lead to development of better therapies for these diseases.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
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Balijepalli, Ravi C
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Columbia University (N.Y.)
Schools of Medicine
New York
United States
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Shuja, Zunaira; Colecraft, Henry M (2018) Regulation of microdomain voltage-gated L-type calcium channels in cardiac health and disease. Curr Opin Physiol 2:13-18
Hu, Zhenyu; Li, Guang; Wang, Jiong-Wei et al. (2018) Regulation of Blood Pressure by Targeting CaV1.2-Galectin-1 Protein Interaction. Circulation 138:1431-1445
Kanner, Scott A; Morgenstern, Travis; Colecraft, Henry M (2017) Sculpting ion channel functional expression with engineered ubiquitin ligases. Elife 6:
Katchman, Alexander; Yang, Lin; Zakharov, Sergey I et al. (2017) Proteolytic cleavage and PKA phosphorylation of ?1C subunit are not required for adrenergic regulation of CaV1.2 in the heart. Proc Natl Acad Sci U S A 114:9194-9199
Aromolaran, Ademuyiwa S; Colecraft, Henry M; Boutjdir, Mohamed (2016) High-fat diet-dependent modulation of the delayed rectifier K(+) current in adult guinea pig atrial myocytes. Biochem Biophys Res Commun 474:554-559
Puckerin, Akil; Aromolaran, Kelly A; Chang, Donald D et al. (2016) hERG 1a LQT2 C-terminus truncation mutants display hERG 1b-dependent dominant negative mechanisms. Heart Rhythm 13:1121-1130
Wan, Elaine; Abrams, Jeffrey; Weinberg, Richard L et al. (2016) Aberrant sodium influx causes cardiomyopathy and atrial fibrillation in mice. J Clin Invest 126:112-22
Joseph, Leroy C; Subramanyam, Prakash; Radlicz, Christopher et al. (2016) Mitochondrial oxidative stress during cardiac lipid overload causes intracellular calcium leak and arrhythmia. Heart Rhythm 13:1699-706
Yang, Lin; Katchman, Alexander; Weinberg, Richard L et al. (2015) The PDZ motif of the ?1C subunit is not required for surface trafficking and adrenergic modulation of CaV1.2 channel in the heart. J Biol Chem 290:2166-74
Morrow, John P; Marx, Steven O (2015) Novel approaches to examine the regulation of voltage-gated calcium channels in the heart. Curr Mol Pharmacol 8:61-8