Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2015:133:47-75.
doi: 10.1016/bs.pmbts.2015.02.002. Epub 2015 Apr 27.

Role of Regulators of G Protein Signaling Proteins in Bone Physiology and Pathophysiology

Joel Jules  1 , Shuying Yang  2 , Wei Chen  1 , Yi-Ping Li  3
Affiliations
Review

Role of Regulators of G Protein Signaling Proteins in Bone Physiology and Pathophysiology

Joel Jules et al. Prog Mol Biol Transl Sci. 2015.

Abstract

Regulators of G protein signaling (RGS) proteins enhance the intrinsic GTPase activity of α subunits of the heterotrimeric G protein complex of G protein-coupled receptors (GPCRs) and thereby inactivate signal transduction initiated by GPCRs. The RGS family consists of nearly 37 members with a conserved RGS homology domain which is critical for their GTPase accelerating activity. RGS proteins are expressed in most tissues, including heart, lung, brain, kidney, and bone and play essential roles in many physiological and pathological processes. In skeletal development and bone homeostasis as well as in many bone disorders, RGS proteins control the functions of various GPCRs, including the parathyroid hormone receptor type 1 and calcium-sensing receptor and also regulate various critical signaling pathways, such as Wnt and calcium oscillations. This chapter will discuss the current findings on the roles of RGS proteins in regulating signaling of key GPCRs in skeletal development and bone homeostasis. We also will examine the current updates of RGS proteins' regulation of calcium oscillations in bone physiology and highlight the roles of RGS proteins in selected bone pathological disorders. Despite the recent advances in bone and mineral research, RGS proteins remain understudied in the skeletal system. Further understanding of the roles of RGS proteins in bone should not only provide great insights into the molecular basis of various bone diseases but also generate great therapeutic drug targets for many bone diseases.

Keywords: Bone; Bone homeostasis; G protein-coupled receptors; G proteins; Osteoblasts; Osteoclasts; PTH/PTHrP; Regulators of G protein signaling; Skeletal disorders; Wnt.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Schematic of GPCR–G protein–RGS activation and inactivation cycle. (A) GPCR inactivation in the absence of ligands. In absence of ligands, Gα is linked to GDP (Gα-GDP) and forms a heterotrimeric complex with the Gγ and Gβ subunits, preventing their liberation to activate effectors to induce cellular response. (B) Ligand-induced GPCR activation. In the presence of ligands, GPCR undergoes a conformational change leading to the activation of Gα through the exchange of GDP for GTP by the receptor GEF activity. Gα-GTP and Gβγ subunits dissociate to modulate the activity of specific effectors to mediate cellular responses. (C) GPCR signaling inactivation by RGS proteins. RGS proteins enhance the GTPase activity of Gα to hydrolyze GTP to GDP leading to the inactivation of the Gα protein and its subsequent reunification with Gβγ subunits to reform the inactive G protein heterotrimeric complex. This prevents the G proteins from continuing activating effectors for cellular response and thus terminates the cellular response. GDP, guanosine diphosphate; GTP, guanosine triphosphate; GEF, guanine nucleotide exchange factor.
Figure 2
Figure 2
Subclassification of RGS family members. All members of the RGS family possess a common RGS domain but are subdivided into different subfamilies based on protein structures. β-Cat, β-catenin-binding; D-AKAP, dual-specificity A-kinase anchoring protein; DEP, dishevelled/EGL-10/pleckstrin; DH, double homology; DIX, dishevelled homology domain; GAIP, Gα interacting protein; GEF, guanine nucleotide exchange factor; GGL, Gγ-like; Goloco, Gαi/o-Loco; GRK, G protein-coupled receptor kinase; GSK, glycogen synthase kinase 3β-binding; PDZ, PSD95/dlg/Z0-1/2; PEST, proline, glutamine, serine, threonine-rich; PH, pleckstrin homology; PP2A, protein phosphatase 2A; PTB, phosphotyrosine-binding; PX, phosphatidylinositol-binding; PXA, PX-associated; RBD, Ras-binding domain; SNX, sorting nexin.
Figure 3
Figure 3
Role of axin in Wnt signaling in bone. (A) In the absence of Wnt ligands, β-catenin is constructively targeted for degradation via a multiprotein destruction complex. β-Catenin is phosphorylated by GSK-3β and then targeted for ubiquitination (Ub) and proteosomal degradation. Axin plays a key role in this process of β-catenin degradation and thus functions as an inhibitor of the canonical Wnt-β pathway. (B) Binding of canonical Wnt ligands to their co-receptors Fz and LRP5/6 prevent β-catenin phosphorylation by GSK-3β, which in turn prevent its degradation and allows it to move to the nucleus to mediate gene expression.
Figure 4
Figure 4
Role of RGS proteins in selected GPCR signaling in bone. In osteoblasts, PTH1R activation upon binding of PTH or PTHrP triggers the activation of the Gαs–AC–cAMP signaling pathway which ultimately promotes osteoblast differentiation. Activation of PTH1R can induce the expression of many RGS proteins, including RGS2 and RGS5. RGS2 can target the cAMP signaling to regulate PTH1R signaling, and RGS5 is likely to regulate osteoblast differentiation by controlling PTH levels. In osteoclasts, activation of GPCRs, such as CasR and OGR1, can activate Gαq or Gαi/o to activate the PLC–Ca2+ signaling pathway for NFATc1 activation or Gαs to activate the Ac–cAMP pathway to promote osteoblast differentiation and function. RGS10, RGS12, and RGS18 can regulate osteoclast differentiation.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Feng X. Chemical and biochemical basis of cell-bone matrix interaction in health and disease. Curr Chem Biol. 2009;3(2):189–196. - PMC - PubMed
    1. Boyce BF, Rosenberg E, de Papp AE, Duong le T. The osteoclast, bone remodelling and treatment of metabolic bone disease. Eur J Clin Invest. 2012;42(12):1332–1341. - PubMed
    1. Asagiri M, Takayanagi H. The molecular understanding of osteoclast differentiation. Bone. 2007;40(2):251–264. - PubMed
    1. Karsenty G. Transcriptional control of skeletogenesis. Annu Rev Genomics Hum Genet. 2008;9:183–196. - PubMed
    1. Karsenty G, Oury F. Biology without walls: the novel endocrinology of bone. Annu Rev Physiol. 2012;74:87–105. - PMC - PubMed

Publication types

LinkOut - more resources