β-Arrestin 2 Mediates G Protein-Coupled Receptor 43 Signals to Nuclear Factor-κB

TGR5 (Takeda G-protein-coupled receptor 5) [also known as GPBAR1 (G-protein-coupled bile acid receptor 1), M-BAR (membrane-type receptor for bile acids) or GPR131 (G-protein-coupled receptor 131)] is a G-protein-coupled receptor that was discovered as a bile acid receptor. TGR5 has specific roles in several tissues, among which are the regulation of energy expenditure, GLP-1 (glucagon-like peptide 1) secretion and gall bladder filling. An accumulating body of evidence now demonstrates that TGR5 also acts in a number of processes important in inflammation. Most striking in this context are several observations that TGR5 signalling curbs the inflammatory response of macrophages via interfering with NF-κB (nuclear factor κB) activity. In line with this, recent animal studies also suggest that TGR5 could be exploited as a potential target for intervention in a number of inflammation-driven diseases, including atherosclerosis. In the present paper, I review our current understanding of TGR5 with a strong focus on its potential as target for intervention in inflammation-driven diseases.

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The receptor activator of nuclear factor κΒ ligand receptor leucine-rich repeat-containing G-protein-coupled receptor 4 contributes to parathyroid hormone–induced vascular calcification

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa290 ◽

2020 ◽

Author(s):

Natalia Carrillo-López ◽

Laura Martínez-Arias ◽

Cristina Alonso-Montes ◽

Beatriz Martín-Carro ◽

Julia Martín-Vírgala ◽

...

Keyword(s):

Parathyroid Hormone ◽

Protein Kinase ◽

G Protein ◽

Vascular Calcification ◽

Nuclear Factor ◽

Leucine Rich Repeat ◽

G Protein Coupled Receptor ◽

Bone Maintenance ◽

Receptor Activator ◽

G Protein Coupled

Abstract Graphical Abstract Background In chronic kidney disease, serum phosphorus (P) elevations stimulate parathyroid hormone (PTH) production, causing severe alterations in the bone–vasculature axis. PTH is the main regulator of the receptor activator of nuclear factor κB (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) system, which is essential for bone maintenance and also plays an important role in vascular smooth muscle cell (VSMC) calcification. The discovery of a new RANKL receptor, leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4), which is important for osteoblast differentiation but with an unknown role in vascular calcification (VC), led us to examine the contribution of LGR4 in high P/high PTH–driven VC. Methods In vivo studies were conducted in subtotally nephrectomized rats fed a normal or high P diet, with and without parathyroidectomy (PTX). PTX rats were supplemented with PTH(1–34) to achieve physiological serum PTH levels. In vitro studies were performed in rat aortic VSMCs cultured in control medium, calcifying medium (CM) or CM plus 10−7 versus 10−9 M PTH. Results Rats fed a high P diet had a significantly increased aortic calcium (Ca) content. Similarly, Ca deposition was higher in VSMCs exposed to CM. Both conditions were associated with increased RANKL and LGR4 and decreased OPG aorta expression and were exacerbated by high PTH. Silencing of LGR4 or parathyroid hormone receptor 1 (PTH1R) attenuated the high PTH–driven increases in Ca deposition. Furthermore, PTH1R silencing and pharmacological inhibition of protein kinase A (PKA), but not protein kinase C, prevented the increases in RANKL and LGR4 and decreased OPG. Treatment with PKA agonist corroborated that LGR4 regulation is a PTH/PKA-driven process. Conclusions High PTH increases LGR4 and RANKL and decreases OPG expression in the aorta, thereby favouring VC. The hormone’s direct pro-calcifying actions involve PTH1R binding and PKA activation.

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