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

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.

Regulator of G Protein Signaling Protein 12 (Rgs12) Controls Mouse Osteoblast Differentiation via Calcium Channel/Oscillation and Gαi-ERK Signaling

“…Ca 2+ , as an intracellular second messenger, impacts nearly every aspect of biological processes through enormous versatility of Ca 2+ signaling . Components of Ca 2+ signaling, including Ca 2+ influx through Ca 2+ channel and Ca 2+ release from intracellular store, regulate the frequency and amplitude of Ca 2+ oscillations, which are critical for promoting osteogenesis . Our results showed that Ca 2+ oscillations were barely detectable in Rgs12 d/d OPCs (Fig.…”

“…Rgs proteins are broadly involved in bone development and remodeling via their influences on OC and OB differentiation and function individually or mutually . Our previous study demonstrated that Rgs12 promotes osteoclastogenesis during bone remodeling .…”

“…We identified Gαi‐ERK signaling as one of the pathway that Rgs12 exerted its regulatory role during osteogenesis. Rgs12 is a GTPase‐activating protein that enhances the intrinsic GTPase activity of Gαi subunit . It has been noted that hyperactivation of the Gαi‐mediated signaling serves as a negative regulator of OB differentiation through inhibitory action on adenylyl cyclase (AC)‐cAMP formation, and eventually leads to a reduction in trabecular bone formation, whereas contrarily, Gαs‐AC‐cAMP signaling is required for OB differentiation .…”

“…The speed and effectiveness of OB precursor cells (OPCs) differentiating into mature OBs determines the rate of bone formation and is dependent on the expression of OB‐specific transcription factors such as runt‐related transcription factor 2 (Runx2) and osterix (Osx), followed by the expression of alkaline phosphatase (ALP) and secretion of extracellular matrix including type 1 collagen (Col1α1) and noncollagenous proteins, leading to the deposition and mineralization of bone matrix . Calcium (Ca 2+ ) oscillations play an indispensable role during these processes through controlling gene expression and affecting OB differentiation and proliferation via Ca 2+ signaling . The excitability of Ca 2+ signaling is determined by the contribution of extracellular Ca 2+ influx, the effect of inositol 1, 4, 5‐trisphosphate (IP3) to release Ca 2+ from the endoplasmic reticulum (ER), and the capacity of removing Ca 2+ from the cytosol by sarcoplasmic/endoplasmic reticulum Ca 2+ ATPase pump (SERCA) and plasma membrane Ca 2+ ATPase (PMCA) .…”

“…It possesses a PSD‐95/Dlg/ZO‐1 (PDZ) domain and a phosphotyrosine‐binding (PTB) domain that are capable of binding the C terminus of G protein–coupled receptors (GPCRs) and interact with GPCR chemokine receptors, respectively, a conserved Rgs domain that is responsible for the GTPase accelerating protein (GAP) activity, a pair of Ras‐binding domains (RBDs) that allows Rgs12 to integrate both heterotrimeric and monomeric G proteins signaling, and a single Gi/o‐Loco (GoLoco) motif that carries guanine nucleotide dissociation inhibitor (GDI) activity toward Gαi subunits, exclusively with Gi1, Gi2, and Gi3, but not Gs, Gq, and Go . This multidomain structure provides Rgs12 with the potential to modulate multiple signaling pathways, including the signaling mediated by Gi‐coupled GPCR, which has been reported to lead to the osteopenia phenotype through the transgenic expression of a constitutively active Gi‐coupled GPCR in OBs . Our previous studies revealed that Rgs12 plays an essential role in osteoclastogenesis through the regulation of PLCγ‐Ca 2+ channel‐Ca 2+ oscillations–nuclear factor of activated T cells 2 (NFAT2) pathways .…”