title: Inositol lipid metabolism and signal transduction in clonal pituitary cells.
abstract: A number of clonal cell lines derived from a rat pituitary tumour, collectively termed GH cells, have retained a range of differentiated cell functions, including their ability to secrete the hormones prolactin and growth hormone in response to stimuli such as thyrotropin-releasing hormone (TRH). The mechanisms underlying this release process involve, at least in part, an increase in cytosolic free calcium levels, and the cells have proved useful as a model system in studies of receptor-controlled calcium mobilization. The initial response of the cells to the addition of TRH now appears to be the interaction of the occupied TRH receptor with a GTP-binding protein. A sophisticated signalling system is then activated which initially involves the phosphodiesteratic hydrolysis of phosphatidylinositol 4,5-bisphosphate to 1,2-diacylglycerol and inositol 1,4,5-trisphosphate. Both of these products are important intracellular messengers, and their formation leads to a plethora of biochemical and electrical changes which culminate in the biphasic release of hormone from the cell. The changes in cytosolic free calcium that occur following TRH addition follow a complex temporal pattern. Within 1 s, the concentration starts to increase from a resting level, in the range 100-150 nmol l-1, to a peak value of around 1 mumol l-1 which is attained within 6-8 s. This 'spike' of calcium is almost exclusively derived from intracellular stores, probably the endoplasmic reticulum, in response to the formation of inositol 1,4,5-trisphosphate. With high concentrations of the peptide, the cytosolic free calcium concentration declines promptly, due to the activation of a protein kinase C-mediated extrusion and/or sequestration process. This inhibitory phase is less marked at low agonist concentrations but, in all cases, is superseded by a second increase in free calcium, which is due to the stimulated influx of the cation through dihydropyridine-sensitive calcium channels. These biphasic changes in calcium, in concert with the activation of protein kinase C, appear sufficient to regulate prolactin secretion.
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D004075:Diglycerides / Q000378:metabolism; D007294:Inositol / Q000378:metabolism*; D015544:Inositol 1,4,5-Trisphosphate; D007295:Inositol Phosphates / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates; D010716:Phosphatidylinositols / Q000378:metabolism*; D010902:Pituitary Gland / Q000378:metabolism*; D010911:Pituitary Neoplasms; D011388:Prolactin / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D011956:Receptors, Cell Surface / Q000378:metabolism; D013973:Thyrotropin-Releasing Hormone / Q000494:pharmacology
chemical_list: D004075:Diglycerides; D007295:Inositol Phosphates; D018129:Phosphatidylinositol Phosphates; D010716:Phosphatidylinositols; D011956:Receptors, Cell Surface; D007294:Inositol; D013973:Thyrotropin-Releasing Hormone; D015544:Inositol 1,4,5-Trisphosphate; D011388:Prolactin; D011493:Protein Kinase C; D002118:Calcium