Abstract
AT1 angiotensin receptor plays important physiological and pathophysiological roles in the cardiovascular system. Renin-angiotensin system represents a target system for drugs acting at different levels. The main effects of ATR1 stimulation involve activation of Gq proteins and subsequent IP3, DAG, and calcium signaling. It has become evident in recent years that besides the well-known G protein pathways, AT1R also activates a parallel signaling pathway through β-arrestins. β-arrestins were originally described as proteins that desensitize G protein-coupled receptors, but they can also mediate receptor internalization and G protein-independent signaling. AT1R is one of the most studied receptors, which was used to unravel the newly recognized β-arrestin-mediated pathways. β-arrestin-mediated signaling has become one of the most studied topics in recent years in molecular pharmacology and the modulation of these pathways of the AT1R might offer new therapeutic opportunities in the near future. In this paper, we review the recent advances in the field of β-arrestin signaling of the AT1R, emphasizing its role in cardiovascular regulation and heart failure.
Highlights
AT1 angiotensin II receptor (AT1R) belongs to the G protein-coupled receptor (GPCR) family of membrane receptors and is activated by the octapeptide hormone, angiotensin II (AngII)
AngII is the main effector of the renin-angiotensin system (RAS), which has pleiotropic effects in the cardiovascular system and salt-water balance regulation
GPCRs usually undergo G protein kinase (GRK) dependent phosphorylation on serine and threonine residues on their C-terminal tails. This phosphorylation leads to binding of β-arrestin proteins, which shut down G protein activation and target the receptors toward internalization
Summary
AT1 angiotensin II receptor (AT1R) belongs to the G protein-coupled receptor (GPCR) family of membrane receptors and is activated by the octapeptide hormone, angiotensin II (AngII). Arrestin Role in AT1R Function proteins leading to inhibition of adenylyl cyclase, activation of phospholipase D, Rho-kinase, and regulation of Ca2+ channels [3, 4] Following their activation, GPCRs usually undergo G protein kinase (GRK) dependent phosphorylation on serine and threonine residues on their C-terminal tails. GPCRs usually undergo G protein kinase (GRK) dependent phosphorylation on serine and threonine residues on their C-terminal tails This phosphorylation leads to binding of β-arrestin proteins, which shut down G protein activation and target the receptors toward internalization. Receptor activation, and PKC mediated phosphorylation of the inactive, unliganded AT1R alone leads to recruitment of β-arrestin, receptor internalization and scaffolding of the signaling complex [24]
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