Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The involvement of atrial natriuretic peptide (ANP) in the regulation of thyroid gland is supported by the presence of high-affinity ANP receptors and the identification of the peptide in thyroid follicular cells. The aim of this work was to study the action of ANP on parameters of thyroid hormone biosynthesis and analyze the intracellular mechanism of the ANP action in cultured bovine thyroid follicles. The addition of ANP (0.1-10 nM) to the culture medium for 24 h inhibited the TSH (thyroid-stimulating hormone)-stimulated iodide uptake with a maximal inhibition at 1 nM ANP. When thyrocytes were incubated with 10 nM ANP the inhibitory effect slightly increased from 24 to 72 h. Thyroglobulin (Tg) mRNA expression was reduced by 1 and 10 nM ANP. After 24 h of treatment with the cGMP analogue, N(2),2'-O-dibutyrylguanosine 3':5'-cyclic monophosphate [(Bu)(2)cGMP] (0.1 and 1 mM), an inhibition of iodide uptake and Tg mRNA expression was obtained, evidencing a cGMP-mediated inhibitory signal in the thyroid cell. A reduction of the cAMP production was induced by incubation of thyroid follicles with 1 and 10 nM ANP for 24 h. Under a similar treatment the cGMP accumulation was increased only by 10 nM ANP. The inhibitory effect of ANP on Tg mRNA level was reverted in the presence of pertussis toxin, an inhibitor of the G(i)-protein-mediated reduction of the adenylate cyclase activity. These results indicate an inhibitory action of ANP on parameters of thyroid hormone biosynthesis. A G(i)-protein-mediated reduction of the cAMP production seems to be the main factor involved in the ANP action although a role of the cGMP pathway should not be discarded specially at high ANP levels.
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PMID:Atrial natriuretic peptide inhibits iodide uptake and thyroglobulin messenger ribonucleic acid expression in cultured bovine thyroid follicles. 1204 6

The thyrotropin (TSH) receptor (TSHR) is a member of the heterotrimeric G protein-coupled family of receptors whose main function is to regulate thyroid cell proliferation as well as thyroid hormone synthesis and release. In this study, we generated a TSHR knockout (TSHR-KO) mouse by homologous recombination for use as a model to study TSHR function. TSHR-KO mice presented with developmental and growth delays and were profoundly hypothyroid, with no detectable thyroid hormone and elevated TSH. Heterozygotes were apparently unaffected. Knockout mice died within 1 week of weaning unless fed a diet supplemented with thyroid powder. Mature mice were fertile on the thyroid-supplemented diet. Thyroid glands of TSHR-KO mice produced uniodinated thyroglobulin, but the ability to concentrate and organify iodide could be restored to TSHR-KO thyroids when cultured in the presence of the adenylate cyclase agonist forskolin. Consistent with this observation was the lack of detectable sodium-iodide symporter expression in TSHR-KO thyroid glands. Hence, by using the TSHR-KO mouse, we provided in vivo evidence, demonstrating that TSHR expression was required for expression of sodium-iodide symporter but was not required for thyroglobulin expression, suggesting that the thyroid hormone synthetic pathway of the mouse could be dissociated into TSHR-dependent and -independent steps.
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PMID:Defining thyrotropin-dependent and -independent steps of thyroid hormone synthesis by using thyrotropin receptor-null mice. 1243 94

Hyperthyroidism is associated with low exercise tolerance despite high cardiac output and sometimes with the development of heart failure. L-type calcium channels may play a role in the mechanism, but this has not been fully understood. We examined the effects of thyroid hormone on gene expression and function of L-type calcium channels in rat ventricles by the ribonuclease protection assay and whole-cell patch-clamp technique, respectively. The effects of bisoprolol, beta-blocking agent, on the regulation of calcium channel by thyroid hormone was also studied. In hyperthyroid animals, the mRNA of the calcium channel alpha1c subunit was reduced on day 4, compared with that in euthyroid animals, and remained low on day 8. Bisoprolol did not affect the thyroid hormone mediated decrease in alpha1c subunit mRNA. While L-type calcium current was greater in hyperthyroid than euthyroid myocytes on day 4, it was smaller on day 8. In addition, the isoproterenol-induced increase in calcium current in euthyroid rats was attenuated in hyperthyroid rats. Acetylcholine decreased calcium current in hyperthyroid myocytes, but not in euthyroid myocytes. In conclusion, L-type calcium current was increased by thyroid hormone in rat ventricular myocytes by the activation of the adenylate cyclase cascade, despite a decreased calcium channel gene expression. These genomic and non-genomic modifications may play an important role in the association of high cardiac output with low exercise tolerance, and in the development of heart failure in hyperthyroidism.
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PMID:Genomic and non-genomic regulation of L-type calcium channels in rat ventricle by thyroid hormone. 1623 92

Thyroperoxidase-catalyzed iodination of thyroglobulin and subsequent oxidative coupling of iodinated tyrosyl residues to protein-bound iodothyronines are the key reactions in thyroid hormone biosynthesis. Under sufficient iodine supply, both synthesis steps are rate-limited by the availability of hydrogen peroxide (H(2)O(2)), which is required as final electron acceptor. The primary enzyme feeding H(2)O(2) to thyroid peroxidase is a heterodimeric NADPH oxidase complex of dual oxidase 2 (DUOX2) and DUOX maturation factor 2 (DUOXA2) at the apical plasma membrane. While the thyrotropin receptor mediates most biological effects through the Gs/adenyl cyclase/cAMP pathway, the Gq/phospholipase C-beta cascade induces H(2)O(2) generation via synergistic effects of increased intracellular calcium and protein kinase C activation on DUOX2/DUOXA2. Defects in thyroidal H(2)O(2) generation have been identified in a subset of patients with congenital hypothyroidism. These include loss-of-function mutations in DUOX2 and DUOXA2. Thyrotropin receptor mutations with preferential loss of Gq-coupling may indirectly affect H(2)O(2) production. Expressivity of the defects can be highly variable owning to the presence of genetic modifiers (e.g., the paralogs DUOX1 and DUOXA1), and environmental factors particularly nutritional iodide intake.
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PMID:Defects of thyroidal hydrogen peroxide generation in congenital hypothyroidism. 2012 87


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