Novel Genetic/Chemogenetic Tools for Studying Beta-Adrenergic Receptors Biased Signaling in Heart Failure

Date
2023-12
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Abstract

Heart failure (HF) is a chronic clinical condition, where the cardiac output is insufficient to meet the needs of the body. Currently, there are several standard pharmacological treatments of HF, most of which are associated with severe side effects, sometimes as detrimental as HF itself. G-protein coupled receptors (GPCRs) are the largest family of cell surface receptors. GPCRs can signal through multiple transducers, including G proteins and β-arrestins, and can be selectively activated in biased response. Cardiac contractility is tightly regulated by the activity of a group of GPCRs, known as Beta-adrenergic receptors. In a normal heart, β1- and β2-adrenoceptors play predominant roles in enhancing excitation-contraction coupling. For the β2AR, at least two signaling pathways have been characterized: the canonical Gαs pathway and the β-arrestin2 (βarr2) pathway. Despite recent advances in our understanding of β2AR biased signaling, much remains to be learned to develop novel therapeutics for the treatment of heart failure. We have designed β2AR-Gαs and β2AR-βarr2 fusion proteins and have shown that expression of these chimeras in AC-16 cells increases the constitutive activity of cAMP and ERK respectively. Our fusion proteins can dissect distinct mechanisms associated with β2AR-Gαs and β2AR-βarr2 signaling pathways and modulate the key regulators of calcium handling and contractile function. Alternatively, previous research has utilized a clozapine-N-oxide (CNO)-sensitive designer GPCR, to selectively induces βarr signaling. I generated and characterized a GPCR designer receptors exclusively activated by designer drugs (DREADD) that selectively binds to β-arrestins (βarr-DREADD). Overall, these experiments will help us to gain mechanistic and functional insight into biased β2AR signaling, and to assess the possibility of using designer GPCRs as a therapeutic approach in the treatment of HF.

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Keywords
Heart failure, G-protein coupled receptors, Beta-Adrenergic Receptors, Biased signaling, Fusion Protein, DREADD
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