GPCR Signaling and Trafficking: The Long and Short of It

Abstract

Emerging findings disclose unexpected components of G protein-coupled receptor (GPCR) signaling and cell biology. Select GPCRs exhibit classical signaling that is restricted to cell membranes and newly described persistent signaling that depends on internalization of the GPCR bound to β-arrestins. Termination of non-canonical endosomal signaling requires intraluminal acidification and sophisticated protein trafficking machineries. Recent studies reveal the structural determinants of the trafficking chaperones. This review summarizes advances in GPCR signaling and trafficking with a focus on the parathyroid hormone receptor as prototype, and the actin-SNX27-retromer tubule complex, an endosomal sorting hub responsible for recycling and preservation of cell surface receptors. The findings are integrated into a model of PTHR trafficking with implications for signal transduction, bone growth, and mineral-ion metabolism.

Barcoding of GPCR trafficking and signaling through the various trafficking roadmaps by compartmentalized signaling networks

“…The extent and mechanism of GPCR internalization have been determined for many GPCR [24]. This review will focus primarily on ß 1 - and ß 2 -adrenergic receptors in order to illustrate the complexities involved in determining the extent and mechanism of GPCR internalization.…”

“…Select members of the A and B families of Gs-coupled GPCR such as V 2 R [141], parathyroid hormone receptor (PTHR) [142], corticotropin releasing hormone receptor 1 [143] and others [144], exhibited both membrane generated down-stream signaling and endosomal ligand-biased persistent signaling that was mediated by activated endosomal Gs and adenylate cyclase [24]. Direct evidence that an endosomal GPCR can activate G proteins to elicit a second wave of signaling was derived from distinct nanobody biosensors that could detect inactive vs. active states of ß 2 -AR or Gs [145].…”

“…These results indicate that type A and type B GPCR differ in their propensity to form complexes between them and ß-arrestin. Class A GPCR, such as the ß 1 - and the ß 2 -AR, interacted transiently or very weakly with ß-arrestin, while class B GPCR, such as V2R and PTHR, interacted tightly with ß-arrestin [24]. Moreover, the specific phosphorylation barcodes of the GPCR that were imprinted by the different GRKs elicited distinct conformational changes in ß-arrestins.…”

Oxidation inhibits PTH receptor signaling and trafficking

“…Furthermore, PTHR endocytosis occurs in a clathrin-dependent manner [45] and clathrin-dependent endocytosis is disrupted under oxidative stress by a mechanism involving tyrosine phosphorylation of clathrin heavy chain [46]. Once the PTHR internalizes into early endosomes, it subsequently traffics to an actin-sorting nexin 27-retromer tubule complex (ASRT), a sorting platform on early endosomes that promotes recycling of surface receptors and has recently been described to mediate rapid PTHR recycling to the surface [41,47,48]. Interestingly, the retromer complex has been described as a target of oxidative stress.…”

A review of antibody-based therapeutics targeting G protein-coupled receptors: an update

“…Alternatively, beta-arrestin assays are also often used in the screening cascade as some GPCRs are also able to signal via G protein independent pathways. Signaling is inactivated by a number of mechanisms, including ligand dissociation, receptor phosphorylation by GPCR kinases (GRKs), beta-arrestin binding and receptor endocytosis [36][37][38]. A number of GPCR-ligand interactions can trigger different signaling pathways with each ligand preferentially activating one pathway over another, i.e., biased signaling [39].…”