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Published January 1996 | Published
Journal Article Open

The human thyrotropin receptor: A heptahelical receptor capable of stimulating members of all four G protein families

Abstract

Thyrotropin is the primary hormone that, via one heptahelical receptor, regulates thyroid cell functions such as secretion, specific gene expression, and growth. In human thyroid, thyrotropin receptor activation leads to stimulation of the adenylyl cyclase and phospholipase C cascades. However, the G proteins involved in thyrotropin receptor action have been only partially defined. In membranes of human thyroid gland, we immunologically identified ɑ subunits of the G proteins G_(s short), G_(s long), Gi_(11), Gi_(12), Gi_(13), G_o (G_(o2) and another form of G_o, presumably G_(o1)), G_q, G_(11), G_(12), and G_(13). Activation of the thyrotropin (TSH) receptor by bovine TSH led to increased incorporation of the photoreactive GTP analogue [ɑ^(-32)P]GTP azidoanilide into immunoprecipitated alpha subunits of all G proteins detected in thyroid membranes. This effect was receptor-dependent and not due to direct G protein stimulation because it was mimicked by TSH receptor-stimulating antibodies of patients suffering from Grave disease and was abolished by a receptor-blocking antiserum from a patient with autoimmune hypothyroidism. The TSH-induced activation of individual G proteins occurred with EC_(50) values of 5-50 milliunits/ml, indicating that the activated TSH receptor coupled with similar potency to different G proteins. When human thyroid slices were pretreated with pertussis toxin, the TSH receptor-mediated accumulation of cAMP increased by approximately ≈ 35% with TSH at 1 milliunits/ml, indicating that the TSH receptor coupled to G_s and G_i. Taken together, these findings show that, at least in human thyroid membranes, in which the protein is expressed at its physiological levels, the TSH receptor resembles a naturally occurring example of a general G protein-activating receptor.

Additional Information

© 1996 National Academy of Sciences. Communicated by Henry R. Bourne, University of California, San Francisco, CA, August 28, 1995 (received for review February 14, 1995). We thank Evelyn Bombien for expert technical assistance, Drs. M. Ludgate and S. Costagliola for providing the high-activity TSH receptor-stimulating and TSH receptor-blocking immunoglobulins, and Drs. Th. Gudermann and B. Nürnberg for critical discussion of the manuscript. This work was supported by the Deutsche Forschungsgemeinschaft, Fonds der Chemischen Industrie, the Belgian Program on Interuniversity Poles of Attraction initiated by the Belgian State, Prime Minister's Office, Federal Service of Science, Technology and Culture, the Fonds National de la Recherche Scientifique (F.N.R.S.-Televie), and the Foundation Rose et Jean Hoguet.

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