Thyrotropic activity of recombinant human glycoprotein hormone analogs and pituitary mammalian gonadotropins in goldfish (Carassius auratus): Insights into the evolution of thyrotropin receptor specificity

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• 作者：T.C. Miller^a ; ^{millertc@mail.nih.gov} ; J.T. Jaques^b ; ^{j-jaques@tvmdl.tamu.edu} ; M.W. Szkudlinski^c ; ^{mszkudlinski@trophogen.com} ; D.S. MacKenzie^a ; ^{duncan@bio.tamu.edu}
• 关键词：TSH ; thyrotropin ; TSH-R ; thyrotropin receptor ; T4 ; thyroxine ; GTH ; gonadotropin ; GSU¦Á ; glycoprotein hormone subunit ¦Á ; LH ; luteinizing hormone ; FSH ; follicle stimulating hormone ; hCG ; human chorionic gonadotropin
• 刊名：General and Comparative Endocrinology
• 出版年：2012
• 出版时间：15 May, 2012
• 年：2012
• 卷：177
• 期：1
• 页码：70-75
• 全文大小：524 K

文摘

Thyrotropin (TSH) is a pituitary glycoprotein hormone heterodimer that binds to its G-protein coupled receptor (TSH-R) at the thyroid to promote the synthesis and secretion of thyroid hormone. Very little is known about TSH-TSH-R interactions in teleost fish. Mammalian gonadotropins have been reported to have an intrinsic ability to activate teleost fish TSH-Rs, suggesting the TSH-R in teleost fish is more promiscuous than in other vertebrates. In this study we utilized the goldfish T₄-release response and recombinant human TSH analogs as in vivo tools to evaluate the structural constraints on hormone-receptor interactions. We found that four positively charged lysines substituted for neutral or negatively charged amino acids within positions 11-20 of the glycoprotein hormone subunit ¦Á (GSU¦Á) significantly increased biological activity of hTSH in fish, as it does in mammals. We further found that bovine follicle stimulating hormone but not luteinizing hormone, whose GSU¦Á subunits also contain four lysine or arginine amino acid residues in the N-terminal portion of GSU¦Á, was thyrotropic in goldfish, suggesting gonadotropin ¦Â subunit contributes to the heterothyrotropic activity. Though recombinant human FSH did not produce a dose-dependent increase in T₄, thyrotropic activity could be acquired with the addition of positively charged amino acids at the N-terminal portion of its GSU¦Á, confirming the importance of the charge on those amino acids for activation of the goldfish TSH-R. These studies demonstrate that mammalian glycoprotein hormone analogs can be utilized to evaluate the conservation of receptor binding and activation mechanisms between fish and mammals.