Role of CaVβ subunits, and lack of functional reserve, in protein kinase a modulation of cardiac CaV1.2 channels

Jayalakshmi Miriyala, Trang Nguyen, David T. Yue, Henry M. Colecraft

Research output: Contribution to journalArticle

Abstract

Protein kinase A (PKA)-mediated enhancement of L-type calcium currents (ICa,L) is essential for sympathetic regulation of the heartbeat and is the classic example of channel regulation by phosphorylation, and its loss is a common hallmark of heart failure. Mechanistic understanding of how distinct CaV channel subunits contribute to PKA modulation of ICa,L has been intensely pursued yet remains elusive. Moreover, critical features of this regulation such as its functional reserve (the surplus capacity available for modulation) in the heart are unknown. Here, we use an overexpression paradigm in heart cells to simultaneously identify the impact of auxiliary CaVβs on PKA modulation of ICa,L and to gauge the functional reserve of this regulation in the heart. CaV1.2 channels containing wild-type β2a or a phosphorylation-deficient mutant (β2a,AAA) were equally upregulated by PKA, discounting a necessary role for β phosphorylation. Nevertheless, channels reconstituted with β2a displayed a significantly diminished PKA response compared with other β isoforms, an effect explainable by a uniquely higher basal Po of β2a channels. Overexpression of all βs increased basal current density, accompanied by a concomitant decrease in the magnitude of PKA regulation. Scatter plots of fold increase in current against basal current density revealed an inverse relationship that was conserved across species and conformed to a model in which a large fraction of channels remained unmodified after PKA activation. These results redefine the role of β subunits in PKA modulation of CaV1.2 channels and uncover a new design principle of this phenomenon in the heart, vis à vis a limited functional reserve.

Original languageEnglish (US)
JournalCirculation Research
Volume102
Issue number7
DOIs
StatePublished - Apr 2008

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Keywords

  • β subunit
  • Ca channel
  • Modulation
  • PKA

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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