Involvement of the Cyclic-AMP-dependent Protein Kinase A Pathway in Thyroxine Effects on Calcitonin Secretion from TT Cells

Abstract

Previous studies have demonstrated that plasma calcitonin is lower in hypothyroid patients and that thyroxine stimulates the human thyroid to release calcitonin. Therefore, thyroid hormones may regulate the secretion of calcitonin, but further work is needed to address this possibility in more detail. TT cells, a model of human thyroid C cells, were incubated in a medium containing vehicle, thyroxine, or thyroxine methyl-hemisuccinate-bovine serum albumin (BSA-L-T₄, thyroxine was immobilized and linked to BSA); then, the levels of secreted calcitonin (hCT), calcitonin mRNA, and cAMP were measured. To study links that connect the cAMP-dependent protein kinase A (PKA) pathway to the observed thyroxine effects, cells were treated with either vehicle or thyroxine plus SQ22536 [an adenylyl cyclase (AC) inhibitor], KT5720 (a PKA inhibitor), or 3-isobutyl-1-methylxanthine (IBMX, a phosphodiesterase inhibitor). The activity levels of AC and PKA, and secreted calcitonin were then measured. The results indicate that thyroxine increases calcitonin secretion, cellular cAMP accumulation, and the activities of AC and PKA, but does not increase hCT mRNA levels in TT cells. BSA-L-T₄ also increases calcitonin secretion. These effects are inhibited by SQ22536, and KT5720 and suggest that the nongenomic thyroxine effects that stimulate calcitonin secretion from TT cells involve the cAMP-dependent PKA pathway.

Key words

C cell - adenylyl cyclase activity - human calcitonin

References

• 1 Carney SL. Calcitonin and human renal calcium and electrolyte transport.  Miner Electrolyte Metab. 1997;  23 43-47
• 2 de Paula FJ, Rosen CJ. Back to the future: revisiting parathyroid hormone and calcitonin control of bone remodeling.  Horm Metab Res. 2010;  42 299-306
• 3 Zabel M, Grzeszkowiak J. Characterisation of thyroid medullary carcinoma TT cell line.  Histol Histopathol. 1997;  12 283-289
• 4 Elisei R. Routine serum calcitonin measurement in the evaluation of thyroid nodules.  Best Pract Res Clin Endocrinol Metab. 2008;  22 941-953
• 5 Body JJ, Demeester-Mirkine N, Borkowski A, Suciu S, Corvilain J. Calcitonin deficiency in primary hypothyroidism.  J Clin Endocrinol Metab. 1986;  62 700-703
• 6 Poppe K, Verbruggen LA, Velkeniers B, Finne E, Body JJ, Vanhaelst L. Calcitonin reserve in different stages of atrophic autoimmune thyroiditis.  Thyroid. 1999;  9 1211-1214
• 7 Borges MF, Abelin NM, Menezes FO, Dahia PL, Toledo SP. Calcitonin deficiency in early stages of chronic autoimmune thyroiditis.  Clin Endocrinol (Oxf). 1998;  49 69-75
• 8 Bugnon C, Fellmann D, Blahser S, Maurat JP, Bloch B. [Immunocytological studies of C cells with anti-calcitonin or antisomatostatin immunoserums in rats treated with vitamin D, thyroxine or benzyl-thiouracil].  C R Seances Soc Biol Fil. 1978;  172 691-696
• 9 Rom-Bugoslavskaia ES, Gopkalova IV. [Effect of thyroid hormones on calcitonin secretion].  Probl Endokrinol (Mosk). 1988;  34 9-13
• 10 Lu C-C, Tsai S-C. The cyclic AMP-dependent protein kinase A pathway is involved in progesterone effects on calcitonin secretion from TT cells.  Life Sci. 2007;  81 1411-1420
• 11 de Bustros A, Ball DW, Peters R, Compton D, Nelkin BD. Regulation of human calcitonin gene transcription by cyclic AMP.  Biochem Biophys Res Commun. 1992;  189 1157-1164
• 12 Krautwurst D, Scherubl H, Kleppisch T, Hescheler J, Schultz G. Dihydropyridine binding and Ca(2+)-channel characterization in clonal calcitonin-secreting cells.  Biochem J. 1993;  289 659-665
• 13 Davis PJ, Davis FB. Nongenomic actions of thyroid hormone.  Thyroid. 1996;  6 497-504
• 14 Incerpi S. Thyroid hormones: rapid reply by surface delivery only.  Endocrinology. 2005;  146 2861-2863
• 15 Farwell AP, Dubord-Tomasetti SA, Pietrzykowski AZ, Leonard JL. Dynamic nongenomic actions of thyroid hormone in the developing rat brain.  Endocrinology. 2006;  147 2567-2574
• 16 Lin HY, Shih A, Davis FB, Davis PJ. Thyroid hormone promotes the phosphorylation of STAT3 and potentiates the action of epidermal growth factor in cultured cells.  Biochem J. 1999;  338 427-432
• 17 Khosravi J, Diamandi A, Mathew G, Muthukumaran N. Intact Human Calcitonin Quantified in Serum with an Immunoenzymometric Assay.  Clin Chem. 1995;  41 s220
• 18 Body JJ, Chanoine JP, Dumon JC, Delange F. Circulating calcitonin levels in healthy children and subjects with congenital hypothyroidism from birth to adolescence.  J Clin Endocrinol Metab. 1993;  77 565-567
• 19 Vierhapper H, Nowotny P, Bieglmayer C, Gessl A. Prevalence of hypergastrinemia in patients with hyper- and hypothyroidism: impact for calcitonin?.  Horm Res. 2002;  57 85-89
• 20 Dadan J, Zbucki RRL, Sawicki B, Bialuk I, Zawadzka A, Winnicka MM, Puchalski Z. Preliminary immunohistochemical investigations of thyroid C cells in an experimental model of hyperthyroidism.  Folia Morphol (Warsz). 2003;  62 319-321
• 21 Dadan J, Zbucki RL, Sawicki B, Winnicka MM, Puchalski Z. Activity of thyroid parafollicular (C) cells in rats with hyperthyroidism--immunohistochemical investigations.  Rocz Akad Med Bialymst. 2004;  49 (S 01) 135-137
• 22 Zamoner A, Heimfarth L, Oliveira Loureiro S, Royer C, Mena Barreto Silva FR, Pessoa-Pureur R. Nongenomic actions of thyroxine modulate intermediate filament phosphorylation in cerebral cortex of rats.  Neuroscience. 2008;  156 640-652
• 23 Lin HY, Thacorf HR, Davis FB, Davis PJ. Potentiation by thyroxine of interferon-gamma-induced antiviral state requires PKA and PKC activities.  Am J Physiol. 1996;  271 C1256-C1261
• 24 Shih A, Zhang S, Cao HJ, Tang H-Y, Davis FB, Davis PJ, Lin H-Y. Disparate effects of thyroid hormone on actions of epidermal growth factor and transforming growth factor-alpha are mediated by 3′,5′-cyclic adenosine 5′-monophosphate-dependent protein kinase II.  Endocrinology. 2004;  145 1708-1717
• 25 Bergh JJ, Lin HY, Lansing L, Mohamed SN, Davis FB, Mousa S, Davis PJ. Integrin alphaVbeta3 contains a cell surface receptor site for thyroid hormone that is linked to activation of mitogen-activated protein kinase and induction of angiogenesis.  Endocrinology. 2005;  146 2864-2871
• 26 Dluzen DE, Ramirez VD. Progesterone effects upon dopamine release from the corpus striatum of female rats. II. Evidence for a membrane site of action and the role of albumin.  Brain Res. 1989;  476 338-344
• 27 Huang YY, Martin KC, Kandel ER. Both protein kinase A and mitogen-activated protein kinase are required in the amygdala for the macromolecular synthesis-dependent late phase of long-term potentiation.  J Neurosci. 2000;  20 6317-6325
• 28 Gamm DM, Baude EJ, Uhler MD. The major catalytic subunit isoforms of cAMP-dependent protein kinase have distinct biochemical properties in vitro and in vivo.  J Biol Chem. 1996;  271 15736-15742
• 29 Krebs EG, Beavo JA. Phosphorylation-dephosphorylation of enzymes.  Annu Rev Biochem. 1979;  48 923-959
• 30 Levitan IB. Modulation of ion channels by protein phosphorylation and dephosphorylation.  Annu Rev Physiol. 1994;  56 193-212
• 31 Montminy MR, Gonzalez GA, Yamamoto KK. Regulation of cAMP-inducible genes by CREB.  Trends Neurosci. 1990;  13 184-188
• 32 Nadine S, Annick J, Françoise L, Claude D, Gérard M, Mohsen SM. Rapid increase of calcitonin-specific mRNA after acute hypercalcemia.  European Journal of Biochemistry. 1984;  139 209-215

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