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Fight-or-flight responses involve β-adrenergic-induced increases in heart rate and contractile force. In the present study, we uncover the primary mechanism underlying the heart's innate contractile reserve. We show that four protein kinase A (PKA)-phosphorylated residues in Rad, a calcium channel inhibitor, are crucial for controlling basal calcium current and essential for β-adrenergic augmentation of calcium influx in cardiomyocytes. Even with intact PKA signaling to other proteins modulating calcium handling, preventing adrenergic activation of calcium channels in Rad-phosphosite-mutant mice (4SA-Rad) has profound physiological effects: reduced heart rate with increased pauses, reduced basal contractility, near-complete attenuation of β-adrenergic contractile response and diminished exercise capacity. Conversely, expression of mutant calcium-channel β-subunits that cannot bind 4SA-Rad is sufficient to enhance basal calcium influx and contractility to adrenergically augmented levels of wild-type mice, rescuing the failing heart phenotype of 4SA-Rad mice. Hence, disruption of interactions between Rad and calcium channels constitutes the foundation toward next-generation therapeutics specifically enhancing cardiac contractility., Competing Interests: Competing interests Columbia University, Harvard University and NY Presbyterian Hospital have filed a patent (WO/2021/003389), which is published and pending review, reporting a FRET-based method for screening small molecules that increase contractility for the treatment of heart failure. Inventors on this patent application are S.O.M., H.M.C., M.K., S.I.Z., A.N.K., M.B.J. and G.L. The FRET-based assay was utilized in this manuscript for assessing the effects of calyculin and whether 3DA-β2B and 2DA-β2B Ca2+ channel subunits bind to Rad.