AKAP12 Signalosome Regulates Cardiac β2-Adrenergic Receptor Signaling



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Heart failure (HF) is a complex clinical syndrome, represented as an impairment in ventricular filling and myocardial blood ejection. As such, HF is one of the leading causes of death in the United States. An extensive network of intertwined intracellular signaling pathways regulates cardiac remodeling (a general determinant of HF). The ability of signalosomes (molecular signaling complexes) to compartmentalize several cellular pathways has been recently established. One example of these signalosomes is a family of scaffolding proteins known as, A Kinase Anchoring Proteins (AKAPs). In cardiomyocytes, the AKAP12 scaffolds a large signalosome that orchestrates spatiotemporal signaling through stabilizing pools of phosphatases and kinases. In addition, it is involved in regulating desensitization, downregulation, and recycling of β Adrenergic Receptors (βAR). Several AKAPs have been associated with cardiac function. AKAPs cardiac expression levels and intracellular distribution are altered under pathological conditions; however, AKAP12 cardiac roles are unclear. In this study, the critical roles of AKAP12 as a scaffold protein in mediating signaling downstream β2AR have been studied using overexpression and downregulation models. In vitro, on a molecular level, we showed that AKAP12 upregulation significantly reduced β2AR internalization and reduced intracellular cAMP levels downstream of the stimulated β2AR. Consequently, on a cellular level, we investigated how AKAP12 upregulation affected cardiomyocyte contractility. We observed that left ventricular cardiomyocytes overexpressing AKAP12 had significantly lower contractility as compared to cardiomyocytes expressing endogenous levels of AKAP12. In line with our in vitro data, we showed in vivo, significantly lower systolic cardiac function in the AKAP12 overexpression mice as compared to wild-type mice. Finally, we observed a significantly higher gene and protein expression of AKAP12 in patients with end-stage HF as compared to non-failing heart patients. Therefore, we conclude that AKAP12 plays a critical role in regulating cardiac contractility downstream β2AR and its upregulation deteriorates cardiac function.



AKAP12, Cardiac function, Beta 2 adrenergic receptor signaling


Portions of this document appear in: Qasim, Hanan, and Bradley K. McConnell. "AKAP12 Signaling Complex: Impacts of Compartmentalizing cAMP‐Dependent Signaling Pathways in the Heart and Various Signaling Systems." Journal of the American Heart Association 9, no. 13 (2020): e016615.