Regulation of Cardiac L-Type Ca 2+ Channel Ca V 1.2 Via the β-Adrenergic-cAMP-Protein Kinase A Pathway Old Dogmas, Advances, and New Uncertainties

• Published in: Circulation research Vol. 113; no. 5; pp. 617 - 631
• Main Authors: Weiss, Sharon, Oz, Shimrit, Benmocha, Adva, Dascal, Nathan
• Format: Journal Article
• Language: English
• Published: 16.08.2013
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.113.301781

In the heart, adrenergic stimulation activates the β-adrenergic receptors coupled to the heterotrimeric stimulatory G s protein, followed by subsequent activation of adenylyl cyclase, elevation of cyclic AMP levels, and protein kinase A (PKA) activation. One of the main targets for PKA modulation is the cardiac L-type Ca 2+ channel (Ca V 1.2) located in the plasma membrane and along the T-tubules, which mediates Ca 2+ entry into cardiomyocytes. β-Adrenergic receptor activation increases the Ca 2+ current via Ca V 1.2 channels and is responsible for the positive ionotropic effect of adrenergic stimulation. Despite decades of research, the molecular mechanism underlying this modulation has not been fully resolved. On the contrary, initial reports of identification of key components in this modulation were later refuted using advanced model systems, especially transgenic animals. Some of the cardinal debated issues include details of specific subunits and residues in Ca V 1.2 phosphorylated by PKA, the nature, extent, and role of post-translational processing of Ca V 1.2, and the role of auxiliary proteins (such as A kinase anchoring proteins) involved in PKA regulation. In addition, the previously proposed crucial role of PKA in modulation of unstimulated Ca 2+ current in the absence of β-adrenergic receptor stimulation and in voltage-dependent facilitation of Ca V 1.2 remains uncertain. Full reconstitution of the β-adrenergic receptor signaling pathway in heterologous expression systems remains an unmet challenge. This review summarizes the past and new findings, the mechanisms proposed and later proven, rejected or disputed, and emphasizes the essential issues that remain unresolved.