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(Circulation Research. 2008;102:e54.)
© 2008 American Heart Association, Inc.

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Role of Ca_Vβ Subunits, and Lack of Functional Reserve, in Protein Kinase A Modulation of Cardiac Ca_V1.2 Channels

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

From the Department of Physiology and Cellular Biophysics (H.M.C.), Columbia University, College of Physicians and Surgeons, New York; and Department of Biomedical Engineering (J.M., T.N., D.T.Y., H.M.C.), Johns Hopkins University, Baltimore, Md.

Correspondence to Henry M. Colecraft, Columbia University, College of Physicians and Surgeons, Department of Physiology and Cellular Biophysics, 630 W 168th St, P&S 7-422, New York, NY 10032. E-mail hc2405{at}columbia.edu

Protein kinase A (PKA)-mediated enhancement of L-type calcium currents (I_Ca,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 Ca_V channel subunits contribute to PKA modulation of I_Ca,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 Ca_Vβs on PKA modulation of I_Ca,L and to gauge the functional reserve of this regulation in the heart. Ca_V1.2 channels containing wild-type β_2a or a phosphorylation-deficient mutant (β_2a,AAA) were equally upregulated by PKA, discounting a necessary role for β phosphorylation. Nevertheless, channels reconstituted with β_2a displayed a significantly diminished PKA response compared with other β isoforms, an effect explainable by a uniquely higher basal P_o of β_2a 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 Ca_V1.2 channels and uncover a new design principle of this phenomenon in the heart, vis à vis a limited functional reserve.

Key Words: Ca channel • β subunit • PKA • modulation

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