Norepinephrine released from sympathetic fibers innervating the heart and epinephrine secreted by adrenal chromaffin cells bind to cardiac β-adrenergic receptors, initiating an intracellular signaling cascade that generates cyclic (c)AMP and activates protein kinase A (PKA), the targets of which control intracellular calcium concentration in cardiomyocytes 1. Under resting conditions, only a fraction of heart pumping power is utilized, but, during stress or exercise, the heart rate and force of contraction increase. The ability of the heart to beat faster and more powerfully is central to this evolutionarily conserved survival instinct. Hence, disruption of interactions between Rad and calcium channels constitutes the foundation toward next-generation therapeutics specifically enhancing cardiac contractility.Īll vertebrates exhibit the ‘fight-or-flight’ response to immediate stress. 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. 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. 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.

In the present study, we uncover the primary mechanism underlying the heart’s innate contractile reserve. Nature Cardiovascular Research volume 1, pages 1022–1038 ( 2022) Cite this articleįight-or-flight responses involve β-adrenergic-induced increases in heart rate and contractile force. Rad regulation of Ca V1.2 channels controls cardiac fight-or-flight response

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