Up-regulation of Endogenous RGS2 Mediates Cross-desensitization between Gs and Gq Signaling in Osteoblasts

Abstract

Regulator of G protein signaling (RGS) proteins limitG protein-coupled receptors (GPCRs) 6 respond to a variety of hormones, paracrine factors, and neurotransmitters by activating heterotrimeric G proteins. Upon activation of the G protein, G␣ is stimulated to exchange bound GDP for cytosolic GTP and is thought to subsequently dissociate from the ␤␥ dimer. Both G␣ and the ␤␥ dimer are then capable of interacting with cellular effectors for a period of time that is limited by the intrinsic GTPase activity of the G␣ subunit. Regulator of G protein signaling (RGS) proteins can reduce the duration of these interactions by increasing the rate of GTP hydrolysis by the G␣ subunits, or by otherwise blocking interactions between G␣ and its target enzymes through a poorly understood process sometimes referred to as "effector antagonism" (1, 2).G protein signaling in osteoblasts is a critical regulator of bone formation. The predominant GPCRs expressed by osteoblasts include the parathyroid hormone (PTH)/parathyroid hormone-related peptide (PTHrP) receptor type 1 (PTH1R), P2Y nucleotide receptors, and prostaglandin receptors (3). Other GPCRs found in osteoblasts include endothelin, adenosine, ␤-adrenergic, angiotensin II, and calcium-sensing receptors (3, 4). Binding of PTH to its specific receptor, PTH1R, predominantly leads to the activation of G s (although under certain conditions the receptor can also couple to G q and G i ) (5, 6). Activated G s stimulates adenylyl cyclase to generate intracellular cAMP, which results in the activation of protein kinase A. Stimulation of G q promotes the activity of phospholipase C-␤ (PLC-␤), resulting in the accumulation of inositol 1,4,5-trisphosphate and diacylglycerol, which lead, respectively, to release of calcium from intracellular stores and activation of protein kinase C. Nucleotide stimulation of P2Y receptors in osteoblasts results in PLC-␤ activation and calcium mobilization, with no effect on adenylyl cyclase (3, 7).

Induction of Regulator of G-Protein Signaling 2 Expression by Long-Acting β2-Adrenoceptor Agonists and Glucocorticoids in Human Airway Epithelial Cells

“…However, for drug development programs to more successfully exploit this pharmacology, it is desirable to comprehensively understand the underlying mechanistic basis. We had previously identified RGS2 as a gene whose expression was increased by glucocorticoids in A549 pulmonary epithelial cells (Chivers et al, 2006), but RGS2 expression is also enhanced by agonists that activate the cAMP signaling cascade (Tsingotjidou et al, 2002;Roy et al, 2006). Because inhaled therapies necessarily impact the airway epithelium, which express both GR and b 2 -adrenoceptors, we selected human bronchial epithelial cells to explore combinatorial effects of these pathways on the expression of RGS2.…”

Age-Related Changes in Bone Morphology Are Accelerated in Group VIA Phospholipase A2 (iPLA2β)-Null Mice

“…Osteoblast differentiation is promoted by RGS2, 86 and iPLA 2 ␤ stimulates transcriptional up-regulation of RGS2 in response to incubating vascular smooth muscle cells with angiotensin II. 54 This transcriptional up-regulation is blocked by pharmacological inhibition of iPLA 2 ␤ with BEL and does not occur in iPLA 2 ␤-null vascular smooth muscle cells.…”

Regulator of G protein signaling 2 mediates cardiac compensation to pressure overload and antihypertrophic effects of PDE5 inhibition in mice

“…For example, it regulates presynaptic Ca 2+ channels via G βγ subunits in neurons (41) and impacts carbachol-stimulated activation of ERK and Akt in COS cells via G i/o interaction (42). RGS2 blunts G s -coupled cAMP accumulation triggered by parathyroid hormone-related peptide (43). However, the effects of RGS2 over G i/o or G s appear to be unimportant in adult cardiac myocytes, as neither muscarinergic nor β-adrenergic cAMP regulation is altered by RGS2 overexpression in contrast to RGS3, RGS4, or RGS5 (6).…”