Location: Cleveland Clinic Main Campus
Beta-adrenergic receptors (beta-ARs) belong to a family of seven transmembrane receptors, also known as the G-protein coupled receptors (GPCRs), that form the interface between the sympathetic nervous system and the cardiovascular system. Beta-ARs are one of the most powerful regulators of cardiac function that are chronically desensitized and downregulated in conditions of heart failure, in part, due to increased phosphorylation of beta-ARs by beta-adrenergic receptor kinase 1 (beta-ARK1). Beta-ARK1 forms a cytosolic complex with phosphoinositide 3-kinase (PI3K) and targets PI3K to the receptor complex following agonist stimulation. Beta-ARK1 targeted PI3K activity at the receptor complex is required for beta-AR internalizaton, as expression of inactive PI3K attenuates receptor internalization. Importantly, cardiac-specific overexpression of inactive PI3K ameliorates cardiac dysfunction in mouse models of heart failure by blocking the receptor of internalization, which seems to result in the preservation of beta-AR function. The underlying mechanism by which preservation of beta-AR function occurs is currently unknown. Identifying the mechanism by which PI3K regulates these protein(s) involved in the preservation of beta-AR function would allow us to develop novel therapeutic interventions for heart failure, or alternatively, could complement the current treatments. We are using a combination of proteomics, transgenic mouse models, and cell culture systems to comprehensively investigate and elucidate the underlying molecular mechanism.
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A Cleveland Clinic study recently published in Circulation Research shows how hypoxia desensitizes receptors in the heart.