Rad regulation of CaV1.2 channels controls cardiac fight-or-flight response
Arianne Papa, Sergey I. Zakharov, Alexander N. Katchman, Jared Kushner, Bi-Xing Chen, Lin Yang, Ao Liu, Alejandro Sanchez Jimenez, Robyn J. Eisert, Gary A. Bradshaw, Wen Dun, Shah Raj Ali, Aaron Rodriques, Karen Zhuqian Zhou, Veli K. Topkara, Mu Yang, John Morrow, Emily J. Tsai, Arthur Karlin, Elaine Y. Wan, Marian Kalocsay, Geoffrey S. Pitt, Henry M. Colecraft, Manu Ben‐Johny, Steven O. Marx
Abstract
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.