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 (PiP2 cascade) and the cAMP cascade. We study here the regulation of the PiP2 cascade by TSH, ATP, NaF, and bradykinin. Our data show that protein iodination and, thus, the synthesis of thyroid hormones in human thyroid is under the control of both the PiP2 cascade and the cAMP cascade. Activation of the PiP2 cascade by TSH (10 mU/mL), NaF, bradykinin, ionomycin, and 12-O-tetradecanoylphorbol-13-acetate stimulates iodide organification. Conversely, activation of the cAMP cascade by forskolin, TSH (0.3 mU/mL), and dibutyryl cAMP inhibits iodide organification. These metabolic effects are correlated to activations and inhibitions of the H2O2-generating system, showing that H2O2 is a limiting factor for protein iodination in these cells. The cascades also regulate in parallel the activity of the pentose phosphate pathway. The effects of various concentrations of TSH on H2O2 generation and [1-14C]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 activation for high concentrations of TSH (that stimulate the PiP2 cascade). The control of thyroid secretion differs from that of protein iodination, in that the cAMP cascade greatly enhances secretion, whereas the PiP2 cascade has no effect on basal secretion and even an inhibitory effect on TSH-stimulated secretion (1 mU/mL). We also demonstrate here the presence of an inhibitory effect of iodide on its own organification in human thyroid (Wolff-Chaikoff effect). This effect is probably mediated through an inhibition of the inositol trisphosphate response to TSH and of the H2O2 response to Ca2+.