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J. Biol. Chem., Vol. 277, Issue 50, 48427-48433, December 13, 2002

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Growth Hormone-induced Diacylglycerol and Ceramide Formation via G_i3 and G in GH4 Pituitary Cells
POTENTIATION BY DOPAMINE-D2 RECEPTOR ACTIVATION^*

Gele Liu, Liliane Robillard, Behzad Banihashemi, and Paul R. Albert

From the Ottawa Health Research Institute, Neuroscience 451 Smyth Road, Room 2464, University of Ottawa, Ottawa, Canada K1H 8M5

Growth hormone (GH) secretion is regulated by indirect negative feedback mechanisms. To address whether GH has direct actions on pituitary cells, lipid signaling in GH₄ZR₇ somatomammotroph cells was examined. GH (EC₅₀ = 5 nM) stimulated diacylglycerol (DAG) and ceramide formation in parallel by over 10-fold within 15 min and persisting for >3 h. GH-induced DAG/ceramide formation was blocked by pertussis toxin (PTX) implicating G_i/G_o proteins and was potentiated 1.5-fold by activation of G_i/G_o-coupled dopamine-D2S receptors, which had no effect alone. Following PTX pretreatment, only PTX-resistant G_i3, not G_o or G_i2, rescued GH-induced DAG/ceramide signaling. GH-induced DAG/ceramide formation was also blocked in cells expressing G blocker GRK-ct. In GH₄ZR₇ cells, GH induced phosphorylation of JAK2 and STAT5, which was blocked by PTX and mimicked by ceramide analogue C2-ceramide or sphingomyelinase treatment to increase endogenous ceramide. We conclude that in GH₄ pituitary cells, GH induces formation of DAG/ceramide via a novel G_i3/G-dependent pathway. This novel pathway suggests a mechanism for autocrine feedback regulation by GH of pituitary function.

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