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G₁₂/G₁₃ Subunits of Heterotrimeric G Proteins Mediate Parathyroid Hormone Activation of Phospholipase D in UMR-106 Osteoblastic Cells

Department of Molecular Pharmacology and Biological Chemistry (A.T.K.S., A.G., J.M.R.-H., P.H.S.), Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611; Cue BIOtech (A.G.), Evanston, Illinois 60201; and Department of Pharmacology (T.V.-Y.), University of Illinois College of Medicine, Chicago, Illinois 60612

Address all correspondence and requests for reprints to: Paula H. Stern, Ph.D., Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Feinberg School of Medicine, 303 East Chicago Avenue S-215, Chicago, Illinois 60611. E-mail: p-stern{at}northwestern.edu.

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 G₁₂ and G₁₃ subunits of heterotrimeric G proteins prevented PTH-stimulated activation of PLD, whereas an antagonist minigene to Gs 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 G₁₂ and G₁₃ activated PLD, an effect that was inhibited by dominant-negative RhoA. The results identify G₁₂ and G₁₃ as upstream transducers of PTH effects on PLD, mediated through RhoA in osteoblastic cells.

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