Context-Dependent Control: PKA Regulation of Vascular CaV1.2 Requires S1928 Not Rad Phosphorylation

Voltage-gated L-type channels, CaV1.2, drive gene expression, cell excitability, and excitation-contraction.1 As central mediators of cardiovascular physiology, CaV1.2 channels represent major therapeutic targets for hypertension, arrhythmias, and heart failure, making calcium channel blockers among the most prescribed cardiovascular medications. CaV1.2 channels undergo regulation through multiple signaling pathways, particularly protein kinase A (PKA). In cardiomyocytes, PKA activation occurs primarily through β-adrenergic receptor signaling, enabling rapid contractile responses to sympathetic stimulation.1 Vascular smooth muscle (VSM) employs the P2Y11/adenylyl cyclase 5 (AC5) axis for PKA activation during diabetic hyperglycemia, a pathological pathway that enhances CaV1.2 activity via S1928 phosphorylation and promotes vascular dysfunction in diabetes.2,3 Recent studies have established phosphorylation-dependent dissociation of the GTPase Rad from CaV1.2 complex as the mechanism for PKA regulation of cardiac CaV1.2.4 However, Rad's role in PKA-mediated vascular CaV1.2 regulation remains unclear, and elucidating this role will advance understanding of tissue-specific regulatory mechanisms and uncover new therapeutic targets.