The secretion of prolactin and growth hormone from the mammalian anterior pituitary gland is modulated by hypophysiotrophic, peripheral and local (paracrine) hormones. The intracellular signals activated or suppressed by hormone receptor stimulation of these pituitary cells are now being characterized, particulary in regard to cyclic AMP accumulation and the hydrolysis of phosphatidylinositol to form inositol-trisphosphate, diacylglycerol and arachidonic acid. diacylglycerol is though to be the natural stimulus for a calcium-phospholipid dependent protein kinase C. We were intrigued to find that receptors strongly associated with the cyclic AMP system (e.g. growth hormone releasing factor) could be rapidly modified by certain phorbol esters (i.e., those that activate protein kinase C). These same phorbol esters could also enhance the exocytosis of prolactin and growth hormone. The normal anterior pituitary gland is endowed with many diverse cell types, all of which express the cyclic AMP and protein kinase C phenotype. Thus, in order to establish the mechanism by which protein kinase C activation can influence hormone receptor stimulated cyclic AMP metabolism in pituitary cells, we have turned to pituitary cell lines to model this positive interaction between C & A kinase-oriented hormone receptor system. Once the best cell type is determined, and the interaction characterized in whole-cell studies, the mechanism will be sought. Indirect actions of phorbolesters include the possibility that phosphodiesterase activity or calcium mobilization are the primary intermediates of phorbol ester action. A direct covalent modification of the hormone receptor-adenylate cyclase system by phorbol ester-induced protein kitanase C activation will also be sought with extensive studies of the influence of GTP, Mg++, Mn++, forskolin and pertussin toxin on adenylate cyclase activity. Once a strong inference about the site(s) of phorbol ester action can be made, the basic findings will be confirmed in normal anterior pituitary cells. These studies ought to provide insight into those systems which use protein kinase C to amplify the cyclic AMP signal induced by an incoming hormone signal to the cells necessary for normal somatic growth after birth and fetility.
| Summers, S T; Cronin, M J (1988) Phorbol esters induce two distinct changes in GH3 pituitary cell adenylate cyclase activity. Arch Biochem Biophys 262:12-8 |
| Weiss, J; Cronin, M J; Thorner, M O (1987) Periodic interactions of GH-releasing factor and somatostatin can augment GH release in vitro. Am J Physiol 253:E508-14 |
