Abstract
βarrestin (βarr)-1 and -2 (βarrs) (or Arrestin-2 and -3, respectively) are universal G protein-coupled receptor (GPCR) adapter proteins expressed abundantly in extra-retinal tissues, including the myocardium. Both were discovered in the lab of the 2012 Nobel Prize in Chemistry co-laureate Robert Lefkowitz, initially as terminators of signaling from the β-adrenergic receptor (βAR), a process known as functional desensitization. They are now known to switch GPCR signaling from G protein-dependent to G protein-independent, which, in the case of βARs and angiotensin II type 1 receptor (AT1R), might be beneficial, e.g., anti-apoptotic, for the heart. However, the specific role(s) of each βarr isoform in cardiac GPCR signaling and function (or dysfunction in disease), remain unknown. The current consensus is that, whereas both βarr isoforms can desensitize and internalize cardiac GPCRs, they play quite different (even opposing in certain instances) roles in the G protein-independent signaling pathways they initiate in the cardiovascular system, including in the myocardium. The present review will discuss the current knowledge in the field of βarrs and their roles in GPCR signaling and function in the heart, focusing on the three most important, for cardiac physiology, GPCR types (β1AR, β2AR & AT1R), and will also highlight important questions that currently remain unanswered.
Highlights
G protein-coupled receptor (GPCR) adapter proteins expressed abundantly in extra-retinal tissues, including the myocardium
Working in mouse hearts that lack β1ARs but express the known GRK2 inhibitor mini-gene βARKct (β1AR−/−/βARKct), we found that this βarr-dependent PDE4D recruitment to the cardiac β2AR is dependent on GRK2 and that it is, sufficient to prevent this β-adrenergic receptor (βAR)
The two βarrs were discovered over two decades ago as plain negative regulators of G protein signaling by GPCRs
Summary
The G protein-coupled receptors (GPCRs) or heptahelical or seven-transmembrane spanning receptors are by far the largest and most diverse superfamily of cell surface receptors. Clathrin/AP-2 binding causes βarr-bound GPCRs to cluster in clathrin-coated pits, which are pinched off the plasma membrane by the motor protein dynamin This βarr-dependent endocytosis (receptor internalization or sequestration) removes receptors from the cell surface, rendering them less responsive to subsequent stimuli. One class exhibits higher affinity for βarr than βarr and forms transient receptor-βarr complexes that dissociate soon after the receptor internalizes These receptors (e.g., the β2AR) rapidly recycle back to the plasma membrane ready to signal again upon the encounter with agonist (receptor resensitization). PP2A [6,11] It is via these interactions that βarr binding to the receptor initiates secondary waves of signal transduction independently of G proteins, usually as the GPCR-βarr complex travels through endosomal compartments during its endocytosis [6]. We will start with an overview of what is currently known about the physiology/pathophysiology of the two cardiac βarrs, and discuss topics pertaining to cardiac βarrs that are currently under intense investigation, highlighting particular areas and questions that await elucidation and answers
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