B₁AR regulation of the Cav1.2 via the SAP97 complex

Beta adrenergic (BAR) signaling is stimulated by the catecholamines norepinephrine (NE) and epinephrine (EPI) to control cardiac contractility. The beta-1-AR (B 1 AR) is the major cardiac subtype. B 1 AR signals canonically through the Ga s subunit, leading to increases in cAMP and PKA; however, it can also signal via the Ga i subunit, leading to increased NOS1, cGMP, and PKG levels. B 1 AR-NOS1 signaling leads to increased contractility and calcium cycling in cardiomyocytes. We found a novel complex within cardiomyocytes in which the B 1 AR, Cav1.2, and NOS1 proteins are held in proximity by the membrane scaffolding protein SAP97. In heart failure, there is a decrease in SAP97 expression and impaired B 1 AR signaling. Cardiac-specific deletion of SAP97 disrupts this complex. In the SAP97-cKO mice, there are minimal changes in B 1 AR-Ga s; however, B 1 AR-Ga i signaling is decreased, with a loss of B 1 AR-NOS1 signaling. Furthermore, we see a decrease in whole cell calcium currents and cardiac contractility. In mice lacking the NOS1, we see the same decrease in calcium currents. We hypothesize SAP97 is necessary to maintain B 1 AR modulation of Cav1.2 in cardiomyocytes. Using electrophysiology and biochemical techniques, we aim to elucidate the role of SAP97 in B 1 AR modulation of Cav1.2 and how this is impacted by the impairment of B 1 AR-Ga i signaling. T32HL086350 RO1-HL147263. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.