Thyroid adenylyl cyclase

Panneels V, Van Sande J, Van den Bergen H, Jacoby C, Braekman JC, Dumont JE, Boeynaems JM (1994) Inhibition of Human Thyroid Adenylyl Cyclase by 2-Iodoalde-hydes. Mol Cell Endocrinol 106 41... 

Figure 25-8. Control of adipose tissue lipolysis. (TSH, thyroid-stimulating hormone FFA, free fatty acids.) Note the cascade sequence of reactions affording amplification at each step. The lipolytic stimulus is "switched off" by removal of the stimulating hormone the action of lipase phosphatase the inhibition of the lipase and adenylyl cyclase by high concentrations of FFA the inhibition of adenylyl cyclase by adenosine and the removal of cAMP by the action of phosphodiesterase. ACTFI,TSFI, and glucagon may not activate adenylyl cyclase in vivo, since the concentration of each hormone required in vitro is much higher than is found in the circulation. Positive ( ) and negative ( ) regulatory effects are represented by broken lines and substrate flow by solid lines.

Because lithium affects second-messenger systems involving both activation of adenylyl cyclase and phosphoinositol turnover, it is not surprising that G proteins are also found to be affected. Several studies suggest that lithium may uncouple receptors from their G proteins indeed, two of lithium s most common side effects, polyuria and subclinical hypothyroidism, may be due to uncoupling of the vasopressin and thyroid-stimulating hormone (TSH) receptors from their G proteins. 

Control of thyroid function via thyroid-pituitary feedback is also discussed in Chapter 37. Briefly, hypothalamic cells secrete thyrotropin-releasing hormone (TRH) (Figure 38-3). TRH is secreted into capillaries of the pituitary portal venous system, and in the pituitary gland, TRH stimulates the synthesis and release of thyrotropin (thyroid-stimulating hormoneTSH). TSH in turn stimulates an adenylyl cyclase-mediated mechanism in the thyroid cell to increase the synthesis and release of T4 and T3. These thyroid hormones act in a negative feedback fashion in the pituitary to block the action of TRH and in the hypothalamus to inhibit the synthesis and secretion of TRH. Other hormones or drugs may also affect the release of TRH or TSH. 

Many of the manifestations of thyroid hyperactivity resemble sympathetic nervous system overactivity (especially in the cardiovascular system), although catecholamine levels are not increased. Changes in catecholamine-stimulated adenylyl cyclase activity as measured by cAMP are found with changes in thyroid activity. Possible explanations include increased numbers of 13 receptors or enhanced amplification of the 13 receptor signal. Other clinical symptoms reminiscent of excessive epinephrine activity (and partially alleviated by adrenoceptor antagonists) include lid lag and retraction, tremor, excessive sweating, anxiety, and nervousness. The opposite constellation of effects is seen in hypothyroidism (Table 38-4). 

Thyrotropin alpha has the biologic properties of pituitary TSH. It binds to TSH receptors on both normal thyroid and differentiated thyroid cancer cells. The TSH-activated receptor stimulates intracellular adenylyl cyclase activity. Increased cAMP production causes increased iodine uptake and increased production of thyroid hormones and thyroglobulin. 

Cannabinoids have been shown to induce cell cycle arrest in breast carcinoma (De Petrocellis et al. 1998), prostate carcinoma (Melck et al. 2000) and thyroid epithelioma cells (Bifulco et al. 2001). In breast carcinoma cells this has been ascribed to the inhibition of adenylyl cyclase and the cAMP/protein kinase A (PKA) pathway (Table 1). PKA phosphorylates and inhibits Raf-1, so cannabinoids prevent the inhibition of Raf-1 and induce prolonged activation of the Raf-l/MEK/ERK signalling cascade (Melck et al 1999). Cannabinoid-induced inhibition of thyroid epithelioma cell proliferation has been attributed to the induction of the cyclin-dependent kinase inhibitor p27 P (Portella et al. 2003). 

Figure 32.2 Inhibitory effects of XI on human thyroid signaling intracellular cascades. R, receptor ATP, adenosine triphosphate nucleotide PuR, purinergic receptor Gs, stimulatory G protein of adenylyl cyclase Gi, inhibitory G protein of adenylyl cyclase Gq, stimulatory G protein of phospholipase C AC, adenylyl cyclase PLC, phospholipase C IPS, inositol 1,4,5-trisphosphate DAG, diacylglycerol PKC, protein kinase C DUOX, dual oxidase PGE, prostaglandin E1 TSHR, TSH receptor cAMP, cyclic 3 -5 adenosine monophosphate PDE, cAMP phosphodiesterase 5 AMP, adenosine monophosphonucleotide cA PK, cAMP-dependent protein kinase FK, forskolin ------> Stimulation inhibition — generation.

Inhibition of thyroid function (effect on p adenylyl cyclase, phospholipase C and HjOj production)... 

In cultured dog thyroid cells, 2-IHDA mimicked the inhibitory effect of iodide on cAMP accumulation (Panneels et ai, 1994b). It also directly inhibited the adenylyl cyclase activity in human thyroid membranes (Panneels et al., 1994b), whereas iodide has no effect on that system (because it is not oxidized by the thyroid peroxidase under the experimental conditions used). These actions of 2-IHDA share the following characteristics of the inhibition of cAMP formation by iodide in intact cells or in membranes prepared from thyroid tissue exposed to iodide (Gochaux et ai, 1987). 

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