ROLE OF THE CYCLIC ADENOSINE-3',5'-MONOPHOSPHATE AND THE PHOSPHATIDYLINOSITOL CA2+ CASCADES IN MEDIATING THE EFFECTS OF THYROTROPIN AND IODIDE ON HORMONE SYNTHESIS AND SECRETION IN HUMAN THYROID SLICES

There are two major known regulatory pathways in human thyrocytes: the phosphatidylinositol-Ca2+ cascade (PiP(2) cascade) and the cAMP casca de. We study here the regulation of the PiP(2) cascade by TSH, ATP, Na F, and bradykinin. Our data show that protein iodination and, thus, th e synthesis of thyroid hormones in human thyroid is under the control of both the PiP(2) cascade and the cAMP cascade. Activation of the PiP (2) cascade by TSH (10 mU/mL), NaF, bradykinin, ionomycin, and 12-0-te tradecanoylphorbol-13-acetate stimulates iodide organification. Conver sely, activation of the cAMP cascade by forskolin, TSH (0.3 mU/mL), an d dibutyryl cAMP inhibits iodide organification. These metabolic effec ts are correlated to activations and inhibitions of the H2O2-generatin g system, showing that H2O2 is a limiting factor for protein iodinatio n in these cells. The cascades also regulate in parallel the activity of the pentose phosphate pathway. The effects of various concentration s of TSH on H2O2 generation and [1-C-14]glucose oxidation were tested, showing a dual effect with an inhibition of these metabolisms for low concentrations of TSH (that stimulate the cAMP cascade) and an activa tion for high concentrations of TSH (that stimulate the PIP2 cascade). The control of thyroid secretion differs from that of protein iodinat ion, in that the cAMP cascade greatly enhances secretion, whereas the PIP2 cascade has no effect on basal secretion and even an inhibitory e ffect on TSH-stimulated secretion (1 mU/mL). We also demonstrate here the presence of an inhibitory effect of iodide on its own organificati on in human thyroid (Wolff-Chaikoff effect). This effect is probably m ediated through an inhibition of the inositol trisphosphate response t o TSH and of the H2O2 response to Ca2+.