TSH

Fluoride = TSH

Background:

During the late 1960s and throughout the 1970s many studies were conducted to investigate the effects of TSH on adenyl cyclase.

At this time dogma was that polypeptide hormones such as TSH produced many of their cellular effects by stimulating adenyl cyclase, thus increasing intracellular cAMP levels (Wolff & Jones, 1971; Wienand and Kohn, 1975).

These studies brought firm evidence that fluoride not only acted like TSH, but fluoride-stimulated cyclase activity was found to be 2 to 5 times higher than the optimal TSH stimulation.

Like TSH, at low levels fluoride stimulated adenyl cyclase activity, while at higher doses it inhibited cyclase activation (Wolff & Jones, 1971; Wienand and Kohn, 1975).

The graphs below were extracted from the study done by Wolff and Jones (1971), documenting the largely identical effects of fluoride and TSH on adenyl cyclase:

Definitions:

Adenyl Cyclase - A membrane-bound enzyme that converts adenosine monophosphate to cyclic adenosine monophosphate (cAMP), an intracellular second messenger.

TSH - Short for thyroid-stimulating-hormone, also called thyrotropin, secreted by the anterior pituitary gland; activates adenyl cyclase (cAMP production) in thyroid cells leading to production and release of the thyroid hormones (T4 and T3). All activity is mediated by G protein activation. The TSH-receptor is the only G-protein-coupled receptor known able to activate all G protein families, an activity directly mimicked by fluoride.

Winand RJ, Kohn LD - "Stimulation of adenylate cyclase activity in retro-orbital tissue membranes by thyrotropin and an exophthalmogenic factor derived from thyrotropin" J Biol Chem 250: 6522 - 6526 (1975)

"As with thyroid plasma membranes (12), fluoride stimulated cyclase activity in retro-orbital tissue plasma membranes is about 2 to 3 times higher than optimal TSH...stimulable cyclase activity. Half-maximal stimulation occurred at 4mM F- under these assay conditions, maximal stimulation was between 8 and 15 mM, and inhibition occurred at greater than 15 mM F - concentrations."

Wolff J, Jones AB - "The Purification of Bovine Thyroid Plasma Membranes and the Properties of Membrane-bound Adenyl Cyclase" J Biol Chem 246:3939 - 3947 (1971)

"Like other mammalian adenyl cyclases, the thyroid membrane preparation was stimulated by F-. Half-maximal stimulation was attained at 2 to 3 mM -under current assay conditions. With 10 mM F- cyclase activity was stimulated 8 to 35 times the basal activity in various preparations and from 2 to 5 times the activity produced by 200 munits of TSH."

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Selected studies using fluoride as TSH analogue:

Bech K, Feldt-Rasmussen U, Madsen SN - "Influence of thyroglobulin on basal and stimulated human thyroid adenylate cyclase activity" J Clin Endocrinol Metab 53(2):264-9 (1981)

Birnbaumer L, Rodbell A - "Adenyl Cyclase in Fat Cells. II. HORMONE RECEPTORS" J Biol Chem 244: 3477 - 3482 (1969)

Clark OH, Gerend PL - "Thyrotropin regulation of adenylate cyclase activity in human thyroid neoplasms" Surgery 97(5):539-46 (1985)

Corvilain B, Laurent E, Lecomte M, Vansande J, Dumont JE - "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" J Clin Endocrinol Metab 79(1):152-9 (1994)

Delemer B, Dib K, Saunier B, Haye B, Jacquemin C, Correze C - "Alteration of the functional activity of Gs protein in thyrotropin-desensitized pig thyroid cells" Mol Cell Endocrinol 75(2):123-31 (1991)

Field JB, Bloom G, Kerins ME, Chayoth R, Zor U - "Activation of protein kinase in thyroid slices by thyroid-stimulating hormone" J Biol Chem
250(13):4903-10 (1975)

Giraud A, Siffroi S, Lanet J, Franc JL - "Binding and internalization of thyroglobulin: selectivity, pH dependence, and lack of tissue specificity" Endocrinology 138(6):2325-32 (1997)

Holmes SD, Titus G, Chou M, Field JB - "Effects of thyrotropin and cholera toxin on the thyroidal adenylate cyclase-adenosine 3',5'-monophosphate system" Endocrinology 107(6):2076-81 (1980)

Jenq SF, Jap TS, Hsieh MS, Chiang H - "The characterization of adenyl cyclase activity in FRTL-5 cell line" Chung Hua I Hsueh Tsa Chih (Taipei) 51(3):159-65 (1993)

Kalderon AE, Sheth V - "Secretion and adenylate cyclase in thyroid nodules" Arch Pathol Lab Med 102(7):381-86 (1978)

Mallet E, Carayon P, Amr S, Brunelle P, Ducastelle T, Basuyau JP, de Menibus CH - "Coupling defect of thyrotropin receptor and adenylate cyclase in a pseudohypoparathyroid patient" J Clin Endocrinol Metab
54(5):1028-32 (1982)

Mizukami Y, Matsubara F, Matsukawa S - "Localization of adenylate cyclase and 5'-nucleotidase activities in human thyroid follicular cells" Histochemistry 74(1):9-19 (1982)

Moore WV, Wolff J - "Thyroid-stimulating hormone binding to beef thyroid membranes. Relation to adenylate cyclase activity" J Biol Chem
249(19):6255-63 (1974)

Nagai Y, Hosoya T - "Properties of the Na+, K+-stimulated adenosine triphosphatase system associated with the plasma membrane of pig thyroid glands" J Biochem (Tokyo) 81(3):721-7 (1977)

Orgiazzi J, Chopra IJ, Solomon DH, Williams DE - "Comparison of the effect of TSH and fluoride on the adenylate cyclase activity of cold thyroid nodules" Ann Endocrinol (Paris) 37(2):107-8 (1976)

Suzuki S, Widnell C, Field JB - "Preparation and characterization of subfractions of bovine thyroid plasma membranes" J Biol Chem
252(9):3074-81 (1977)

Toccafondi RS, Rotella CM, Tanini A, Fani P, Arcangeli P - "Thyrotrophin-responsive adenylate cyclase activity in thyroid toxic adenoma" Acta Endocrinol (Copenh) 92(4):658-68 (1979)

Tomura H, Itoh H, Sho K, Sato K, Nagao M, Ui M, Kondo Y, Okajima F - "Betagamma subunits of pertussis toxin-sensitive G proteins mediate A1 adenosine receptor agonist-induced activation of phospholipase C in collaboration with thyrotropin. A novel stimulatory mechanism through the cross-talk of two types of receptors" J Biol Chem 272(37):23130-7 (1997)

Totsuka Y, Nielsen TB, Field JB - "Effect of thyrotropin-induced desensitization of bovine thyroid adenylate cyclase on the nucleotide regulatory protein" Endocrinology 113(3):1088-95 (1983)

Walinder O, Karlsson FA, Dahlberg PA - "Adenyl cyclase activity in human thyroid plasma membranes from normal human thyroid tissue and thyroid adenomas" Acta Endocrinol (Copenh) 92(1):95-104 (1979)

Wolff J, Jones AB - "The Purification of Bovine Thyroid Plasma Membranes and the Properties of Membrane-bound Adenyl Cyclase" J Biol Chem 246:3939 - 3947 (1971)

Wolff J, Cook GH - "Activation of thyroid membrane adenylate cyclase by purine nucleotides" J Biol Chem 10;248(1):350-5 (1973)

Wolff J, Cook GH - "Charge effects in the activation of adenylate cyclase" J Biol Chem 10;250(17):6897-903 (1975)

Yamashita K, Field JB - "Elevation of cyclic guanosine 3',5'-monophosphate levels in dog thyroid slices caused by acetylcholine and sodium fluoride"
J Biol Chem 247(21):7062-6 (1972)

Zor U, Kaneko T, Lowe IP, Bloom G, Field JB - "Effect of thyroid-stimulating hormone and prostaglandins on thyroid adenyl cyclase activation and cyclic adenosine 3',5',-monophosphate" J Biol Chem 244(19):5189-95 (1969)