Thyroid hormones adenylate cyclase

Many of the adverse effects of lithium can be ascribed to the action of lithium on adenylate cyclase, the key enz)nne that links many hormones and neurotransmitters with their intracellular actions. Thus antidiuretic hormone and thyroid-stimulating-hormone-sensitive adenylate cyclases are inhibited by therapeutic concentrations of the drug, which frequently leads to enhanced diuresis, h)rpoth)n oidism and even goitre. Aldosterone synthesis is increased following chronic lithium treatment and is probably a secondary consequence of the enhanced diuresis caused by the inhibition of antidiuretic-hormone-sensitive adenylate cyclase in the kidney. There is also evidence that chronic lithium treatment causes an increase in serum parathyroid hormone levels and, with this, a rise in calcium and magnesium concentrations. A decrease in plasma phosphate and in bone mineralization can also be attributed to the effects of the drug on parathyroid activity. Whether these changes are of any clinical consequence is unclear. 

The secretion of thyroid hormones starts with endocy-tosis of the modified thyroglobulin, followed by fusion of the endocytotic vesicles with lysosomes. The lysosomal enzymes then degrade the thyroglobulin, liberating triiodothyronine and thyroxine into the circulation. Only about five molecules of T3 and T4 are generated from each molecule of thyroglobulin. Thyroid hormone secretion is stimulated by thyrotropin (TSH), a pituitary hormone that activates adenylate cyclase in its target cells. 

Gs Epinephrine, norepinephrine, histamine, glucagon, ACTH, luteinizing hormone, follicle-stimulating hormone, thyroid-stimulating hormone, and others Adenylate cyclase Ca2+ channels... 

Effects of thyroid hormone on the receptor-adenylate cyclase system in the adipocyte and the hepatocyte... 

Fig. 4. Action of thyroid hormones on cyclic AMP production and degradation in the adipocyte. The response of the adipocyte to different lipolytic hormones (/3 catecholamines, ACTH and glucagon) is under thyroid hormone control both at the level of the receptor-adenylate cyclase complex and at the level of the phosphodiesterase. T, also regulates the expression of several key lipogenic enzymes.

Recently Exton and co-workers [93] have proposed that adrenergic responsiveness in skeletal muscle is regulated by thyroid hormones at two levels, i.e., 1) stimulation of /3-adrenergic receptors and adenylate cyclase activity and 2) increased activity of phosphoprotein phosphatases. Such results would explain the effect of thyroid hormones on glycogen metabolism in muscle although the primary mechanism of these actions remains unknown. 

TSH binds a G protein-coupled receptor to activate adenylate cyclase and trigger a signaling cascade leading to thyroid hormone biosynthesis. 

P2. Pastan, I., and Katzen, R., Activation of adenyl-cyclase in thyroid homogenate by thyroid stimulating hormone. Biochem. Biophys. Res. Commun. 29, 792-798 (1967). 

Lithium salts have been used as safe adjuncts In the Initial treatment of thyrotoxicosis (75). Lithium Is concentrated by the thyroid gland (76), with a thyrold-to-serum ratio of more than 2 1, suggesting active transport. Lithium Ion Inhibits adenylate cyclase, which forms cAMP. Formed In response to TSH, cAMP Is a stimulator of the processes Involved In thyroid hormone release from the gland. Inhibition of hormone secretion by lithium has proved to be a useful adjunct In treatment of hyperthyroidism (77). 

Levey GS, Epstein SE. Myocardial adenyl cyclase activation by thyroid hormones and evidence for two adenyl cyclase systems. J Clin Invest 1969 48 1663-1669. 

PGE can stimulate or inhibit its own hormone-induced synthesis via an ability to stimulate cAMP production. In the canine renal collecting tubule there appear to be two PGE receptors ". One of these receptors is an inhibitory receptor which modulates vasopressin-induced H2O flow . The other receptor is coupled to stimulation of adenylate cyclase activity. This latter receptor may be involved in inhibition of arachidonate release and feedback inhibition of hormone-induced PGE production. Similarly, neutrophil activation (and PGE2 synthesis) induced by f-met-leu-phe is under feedback inhibitory control by a PGE receptor apparently coupled to The opposite situation occurs in the thyroid. In the thyroid, there are two phases to PGE synthesis. The second phase is cAMP dependent and PGE serves to augment its own synthesis by its ability to stimulate adenylate cyclase activity ... 

The thyroid releasing hormone binds to receptors in the pituitary and like many other hormones activates adenyl cyclase and increases the intracellular levels of cyclic AMP. 

In Table 2a are listed a number of receptors which both produce a PI response and, by the criteria mentioned above, seem to produce their major effects on target tissues through effects on the intracellular Ca " concentration. Most have been listed and reviewed previously (2), but thyrotrophin deserves some special comment since it is a hormone whose effects are usually ascribed mainly to activation of adenylate cyclase (see 32). Although this is undoubtedly correct, there is also some evidence that certain effects of thyrotrophin, particularly stimulation of glucose oxidation and of protein iodination, are triggered by a Ca " influx into thyroid cells (45). 

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