PROTEIN-KINASE C-DEPENDENT GROWTH-HORMONE RELEASING PEPTIDES STIMULATE CYCLIC ADENOSINE-3',5'-MONOPHOSPHATE PRODUCTION BY HUMAN PITUITARY SOMATOTROPINOMAS EXPRESSING GSP ONCOGENES - EVIDENCE FOR CROSS-TALK BETWEEN TRANSDUCTION PATHWAYS

The effects of the synthetic GH-releasing peptides, GHRP-2 and GHRP-6, on phosphatidylinositol (PI) hydrolysis and cAMP production have been examined in human pituitary somatotropinomas with and without adenyly l cyclase-activating gsp oncogenes. Both peptides dose-dependently sti mulated the rate of PI hydrolysis and GH secretion by cell cultures of both types of somatotropinoma. GHRP-2 was considerably more potent th an GHRP-6, The effects on GH secretion were reduced or abolished by ph loretin, an inhibitor of protein kinase C, and W7, an inhibitor of cal modulin, However, antagonism of the GHRH-receptor and of protein kinas e A with (N-Ac-Tyr(1),D-Arg(2))GRF-(1-29)-NH2 and Rp-adenosine-3',5'-c yclic monophosphothioate, respectively, did not alter the stimulatory effects of GHRP-2 and GHRP-6 on GH secretion, The effect of GHRP-2 and /or GHRP-6 on cAMP production was studied in 15 tumors, seven of which possessed constitutive adenylyl cyclase activity as evidenced by pres ence of gsp oncogenes. Both peptides stimulated cAMP production in the latter but not former types of tumor. Moreover, GHRP-2 and GHRP-6 pot entiated the stimulation of cAMP production induced by GHRH and pituit ary adenylate cyclase-activating polypeptide in tumors without gsp onc ogenes. These results demonstrate that GHRP-2 and GHRP-6 exert identic al effects on human pituitary somatotropinomas, except for differences in potency. Additionally, under conditions of adenylyl cyclase activi ty above basal levels (i.e. through stimulation of G(s)-protein couple d receptors or because of gsp oncogene expression), cAMP production ca n be increased even further by GHRP, providing evidence for cross-talk between the PI and adenylyl cyclase transduction systems in pituitary cells.