학술논문
Rad regulation of CaV 1.2 channels controls cardiac fight-or-flight response
Document Type
Original Paper
Author
Papa, Arianne; Zakharov, Sergey I.; Katchman, Alexander N.; Kushner, Jared S.; Chen, Bi-xing; Yang, Lin; Liu, Guoxia; Jimenez, Alejandro Sanchez; Eisert, Robyn J.; Bradshaw, Gary A.; Dun, Wen; Ali, Shah R.; Rodriques, Aaron; Zhou, Karen; Topkara, Veli; Yang, Mu; Morrow, John P.; Tsai, Emily J.; Karlin, Arthur; Wan, Elaine; Kalocsay, Marian; Pitt, Geoffrey S.; Colecraft, Henry M.; Ben-Johny, Manu; Marx, Steven O.
Source
Nature Cardiovascular Research. 1(11):1022-1038
Subject
Language
English
ISSN
2731-0590
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.
Papa et al. show that phosphorylation by PKA of four residues in Rad, a calcium channel inhibitor, is required to mediate the β-adrenergic-induced increase in calcium current and contractile force. Additionally, Rad-phosphosite-mutant mice showed reduced basal heart rate and contractility. Conversely, expression of mutant calcium channel unable to bind wild-type or phosphosite-mutant Rad was sufficient to enhance basal calcium influx and contractility, independently of β-adrenergic stimulation.
Papa et al. show that phosphorylation by PKA of four residues in Rad, a calcium channel inhibitor, is required to mediate the β-adrenergic-induced increase in calcium current and contractile force. Additionally, Rad-phosphosite-mutant mice showed reduced basal heart rate and contractility. Conversely, expression of mutant calcium channel unable to bind wild-type or phosphosite-mutant Rad was sufficient to enhance basal calcium influx and contractility, independently of β-adrenergic stimulation.