TY - JOUR
T1 - Gα12/Gα13 subunits of heterotrimeric G proteins mediate parathyroid hormone activation of phospholipase D in UMR-106 osteoblastic cells
AU - Singh, A. T.K.
AU - Gilchrist, A.
AU - Voyno-Yasenetskaya, T.
AU - Radeff-Huang, J. M.
AU - Stern, P. H.
PY - 2005/5
Y1 - 2005/5
N2 - PTH, a major regulator of bone remodeling and a therapeutically effective bone anabolic agent, stimulates several signaling pathways in osteoblastic cells. Our recent studies have revealed that PTH activates phospholipase D (PLD) -mediated phospholipid hydrolysis through a RhoA-dependent mechanism in osteoblastic cells, raising the question of the upstream link to the PTH receptor. In the current study, we investigated the role of heterotrimeric G proteins in mediating PTH-stimulated PLD activity in UMR-106 osteoblastic cells. Transfection with antagonist minigenes coding for small peptide antagonists to Gα12 and Gα13 subunits of heterotrimeric G proteins prevented PTH-stimulated activation of PLD, whereas an antagonist minigene to Gαs failed to produce this effect. Effects of pharmacological inhibitors (protein kinase inhibitor, Clostridium botulinum exoenzyme C3) were consistent with a role of Rho small G proteins, but not of cAMP, in the effect of PTH on PLD. Expression of constitutively active Gα12 and Gα13 activated PLD, an effect that was inhibited by dominant-negative RhoA. The results identify Gα12 and Gα13 as upstream transducers of PTH effects on PLD, mediated through RhoA in osteoblastic cells.
AB - PTH, a major regulator of bone remodeling and a therapeutically effective bone anabolic agent, stimulates several signaling pathways in osteoblastic cells. Our recent studies have revealed that PTH activates phospholipase D (PLD) -mediated phospholipid hydrolysis through a RhoA-dependent mechanism in osteoblastic cells, raising the question of the upstream link to the PTH receptor. In the current study, we investigated the role of heterotrimeric G proteins in mediating PTH-stimulated PLD activity in UMR-106 osteoblastic cells. Transfection with antagonist minigenes coding for small peptide antagonists to Gα12 and Gα13 subunits of heterotrimeric G proteins prevented PTH-stimulated activation of PLD, whereas an antagonist minigene to Gαs failed to produce this effect. Effects of pharmacological inhibitors (protein kinase inhibitor, Clostridium botulinum exoenzyme C3) were consistent with a role of Rho small G proteins, but not of cAMP, in the effect of PTH on PLD. Expression of constitutively active Gα12 and Gα13 activated PLD, an effect that was inhibited by dominant-negative RhoA. The results identify Gα12 and Gα13 as upstream transducers of PTH effects on PLD, mediated through RhoA in osteoblastic cells.
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UR - http://www.scopus.com/inward/citedby.url?scp=17744388606&partnerID=8YFLogxK
U2 - 10.1210/en.2004-1283
DO - 10.1210/en.2004-1283
M3 - Article
C2 - 15705779
AN - SCOPUS:17744388606
SN - 0013-7227
VL - 146
SP - 2171
EP - 2175
JO - Endocrinology
JF - Endocrinology
IS - 5
ER -