βArrestins in Cardiac G Protein-Coupled Receptor Signaling and Function: Partners in Crime or “Good Cop, Bad Cop”?

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.

Adaptive Activation of a Stress Response Pathway Improves Learning and Memory Through Gs and β-Arrestin-1–Regulated Lactate Metabolism

“…In particular, these results suggest that signaling through a combination of a specific receptor and a specific arrestin subtype may function differently in different brain regions to finely control cognitive functions. The present results, together with recent research on cardiac systems, add to the list of functional divergences between the different arrestin isoforms (38–40). …”

Loss of β-arrestin1 expression predicts unfavorable prognosis for non-small cell lung cancer patients

“…As reported by several former reviews [20][21][22], although β-arrestin1 and β-arrestin2 show high (about 78 %) amino acid homology and exhibit similar functions in regulating GPCRs signaling, they still have distinct functions in the progression of one specific cancer type, such as lung cancer. Their functional disparities might be explained by the minor differences in their sequences [16].…”

GPCR signaling and cardiac function

“…Recent studies by us and others have indicated that, in the heart, βarrestin1 desensitizes β-receptors and thus, reduces β-receptor-dependent contractility, whereas βarrestin2-dependent signaling might actually promote β 1 -receptor-dependent contractility without affecting this receptor's classical desensitization ( Fig. 1) Watari et al, 2013;Lymperopoulos and Negussie, 2013;Lymperopoulos A., unpublished data).…”