Regulation of cardiac L-Type Ca2+ channel CaV1.2 via the β-adrenergic-cAMP-protein kinase a pathway: Old dogmas, advances, and new uncertainties

Sharon Weiss*, Shimrit Oz, Adva Benmocha, Nathan Dascal

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

Abstract

In the heart, adrenergic stimulation activates the β-adrenergic receptors coupled to the heterotrimeric stimulatory Gs 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 channel (CaV1.2) located in the plasma membrane and along the T-tubules, which mediates Ca entry into cardiomyocytes. β-Adrenergic receptor activation increases the Ca current via CaV1.2 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 CaV1.2 phosphorylated by PKA, the nature, extent, and role of post-translational processing of CaV1.2, 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 current in the absence of β-adrenergic receptor stimulation and in voltage-dependent facilitation of CaV1.2 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.

Original languageEnglish
Pages (from-to)617-631
Number of pages15
JournalCirculation Research
Volume113
Issue number5
DOIs
StatePublished - 16 Aug 2013

Keywords

  • adrenergic
  • calcium channels
  • cyclic AMP-dependent protein kinases
  • heart
  • molecular mechanism

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