Tyrosine kinase inhibitors enhance GHRH-stimulated cAMP accumulation and GH release in rat anterior pituitary cells.
In this study, the role of tyrosine phosphorylation in agonist-stimulated cAMP accumulation and GH release in rat anterior pituitary cells was investigated. It was found that genistein, a tyrosine kinase inhibitor, while having no effect on its own, potentiated GHRH-stimulated cAMP accumulation in a concentration-dependent manner. In comparison, daidzein, an inactive analogue of genistein, was ineffective and vanadate, a phosphotyrosine phosphatase inhibitor, reduced GHRH-stimulated cAMP accumulation. Additional structurally unrelated tyrosine kinase inhibitors, erbstatin and tyrphostins, also potentiated GHRH-stimulated cAMP accumulation. To determine the site of action of the tyrosine kinase inhibitors, pituitary adenylate cyclase-activating polypeptide (PACAP), cholera toxin and forskolin were used to increase cAMP accumulation. Genistein enhanced the PACAP-, cholera toxin- or forskolin-stimulated cAMP accumulation, suggesting that the site of action is at the post-receptor level. However, when the phosphodiesterase was inhibited by isobutylmethylxanthine, genistein did not potentiate and vanadate did not inhibit GHRH-stimulated cAMP accumulation, indicating that phosphodiesterase is a probable site of action for the inhibitor. Genistein and erbstatin also enhanced GHRH-stimulated GH release and the effect of vanadate was inhibitory. These results indicate that tyrosine kinase inhibitors enhance cAMP accumulation through their action on phosphodiesterase activity in rat anterior pituitary cells and the tyrosine kinase pathway appears to be involved in the control of GH release.
Ogiwara
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Department of Physiology, Faculty of Medicine, University of Alberta, Edmonton, Canada.
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D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000032:analysis / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D019833:Genistein; D013006:Growth Hormone / Q000032:analysis / Q000378:metabolism*; D013007:Growth Hormone-Releasing Hormone / Q000494:pharmacology*; D006873:Hydroquinones / Q000494:pharmacology; D007529:Isoflavones / Q000494:pharmacology*; D008297:Male; D009570:Nitriles / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010903:Pituitary Gland, Anterior / Q000187:drug effects* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014638:Vanadates / Q000494:pharmacology
D006873:Hydroquinones; D007529:Isoflavones; D009570:Nitriles; D010726:Phosphodiesterase Inhibitors; D014638:Vanadates; D013006:Growth Hormone; D013007:Growth Hormone-Releasing Hormone; D019833:Genistein; D000242:Cyclic AMP; D011505:Protein-Tyrosine Kinases; C048212:erbstatin