Attenuation of pituitary polyphosphoinositide metabolism by protein kinase C activation.
Phorbol myristate acetate (PMA) stimulates pituitary hormone release by activating protein kinase C (PKC). By doing so, PMA mimics the diacylglycerol (DAG) produced by the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2). The present study demonstrates that PMA and DAG augment prolactin release and attenuate the elevations of inositol phosphates (IPX) elicited by thyrotropin-releasing hormone (TRH), angiotensin II, neurotensin, bombesin and gonadotropin-releasing hormone (GnRH) in normal anterior pituitary and prolactin-secreting 7315a tumor cells. 4 alpha-Phorbol 12,13-didecanoate (PDD), an inactive analog of PMA, was found to have no effect on IPX levels; the PKC inhibitor H-7 attenuated the PMA-related inhibition of TRH-induced IPX. To examine whether PMA attenuates IPX generation or increases IPX metabolism, the effects of PMA on the levels of inositol phosphates and phosphoinositides were determined. TRH increased inositol trisphosphate, inositol bisphosphate and inositol monophosphate, and decreased PIP2 and phosphatidylinositol 4-phosphate levels. PMA had no effect on basal phosphoinositide or inositol phosphate levels, but attenuated the effects of TRH on these parameters. Thus PMA and DAG, by a mechanism involving PKC-mediated attenuation of secretagogue-induced hydrolysis of PIP2, decreases IPX production, and therefore PKC activation may exert negative feedback regulation on anterior pituitary secretory activity.
Judd
A M
AM
Department of Internal Medicine, University of Virginia School of Medicine, Charlottesville 22908.
Jarvis
W D
WD
MacLeod
R M
RM
D000818:Animals; D002118:Calcium / Q000032:analysis; D004075:Diglycerides / Q000494:pharmacology; D004789:Enzyme Activation; D005260:Female; D007295:Inositol Phosphates / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates; D010716:Phosphatidylinositols / Q000378:metabolism*; D010902:Pituitary Gland / Q000378:metabolism*; D011493:Protein Kinase C / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013973:Thyrotropin-Releasing Hormone / Q000494:pharmacology
D004075:Diglycerides; D007295:Inositol Phosphates; D018129:Phosphatidylinositol Phosphates; D010716:Phosphatidylinositols; C044295:1,2-dioctanoylglycerol; D013973:Thyrotropin-Releasing Hormone; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium