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Redox and proteolytic regulation of cardiomyocyte β-adrenergic receptors - a novel paradigm for the regulation of catecholamine responsiveness in the heart.
Front Immunol
December 2023
Department of Molecular Pharmacology and Therapeutics, Columbia University, New York, NY, United States.
Conventional models view β-adrenergic receptors (βARs) as full-length proteins that activate signaling pathways that influence contractile function and ventricular remodeling - and are susceptible to agonist-dependent desensitization. This perspective summarizes recent studies from my laboratory showing that post-translational processing of the β-adrenergic receptor N-terminus results in the accumulation of both full-length and N-terminally truncated forms of the βAR that differ in their signaling properties. We also implicate oxidative stress and βAR cleavage by elastase as two novel mechanisms that would (in the setting of cardiac injury or inflammation) lead to altered or decreased βAR responsiveness.
View Article and Find Full Text PDFBeta-Adrenergic Receptor Cleavage and Regulation by Elastase.
JACC Basic Transl Sci
August 2023
Department of Pharmacology, Columbia University, New York, New York, USA.
The decrease in β-adrenergic receptor responsiveness in heart failure is attributed conventionally to agonist-dependent desensitization. We identify elastase-dependent β-adrenergic receptor cleavage as a novel proteolytic mechanism that disrupts β-adrenergic receptor responsiveness in the setting of tissue injury or inflammation.
View Article and Find Full Text PDFGTPγS Assay for Measuring Agonist-Induced Desensitization of Two Human Polymorphic Alpha-Adrenoceptor Variants.
Methods Mol Biol
September 2022
Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL, USA.
α-Adrenergic receptors (ARs) mediate many cellular actions of epinephrine and norepinephrine, including inhibition of their secretion (sympathetic inhibition) from adrenal chromaffin cells. Like many other G protein-coupled receptors (GPCRs), they undergo agonist-dependent phosphorylation and desensitization by GPCR kinases (GRKs), a phenomenon recently shown to play a major role in the sympathetic overdrive that accompanies and aggravates chronic heart failure. A three-glutamic acid deletion polymorphism in the human α-AR subtype gene (Glu301-303) causes impaired agonist-promoted receptor phosphorylation and desensitization, resulting in enhanced signaling to inhibition of cholinergic-induced catecholamine secretion in adrenal chromaffin cells.
View Article and Find Full Text PDFDetermining the Effects of Differential Expression of GRKs and β-arrestins on CLR-RAMP Agonist Bias.
Front Physiol
March 2022
Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom.
Signalling of the calcitonin-like receptor (CLR) is multifaceted, due to its interaction with receptor activity modifying proteins (RAMPs), and three endogenous peptide agonists. Previous studies have focused on the bias of G protein signalling mediated by the receptor and receptor internalisation of the CLR-RAMP complex has been assumed to follow the same pattern as other Class B1 G Protein-Coupled Receptors (GPCRs). Here we sought to measure desensitisation of the three CLR-RAMP complexes in response to the three peptide agonists, through the measurement of β-arrestin recruitment and internalisation.
View Article and Find Full Text PDFResidency time of agonists does not affect the stability of GPCR-arrestin complexes.
Br J Pharmacol
August 2022
Institute of Pharmacology and Clinical Pharmacy, Philipps-University Marburg, Marburg, Germany.
Background And Purpose: The interaction of arrestins with G-protein coupled receptors (GPCRs) desensitizes agonist-dependent receptor responses and often leads to receptor internalization. GPCRs that internalize without arrestin have been classified as "class A" GPCRs whereas "class B" GPCRs co-internalize with arrestin into endosomes. The interaction of arrestins with GPCRs requires both agonist activation and receptor phosphorylation.
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