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J. Biol. Chem., Vol. 281, Issue 19, 13103-13109, May 12, 2006

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Low Affinity Analogs of Thyrotropin-releasing Hormone Are Super-agonists^*

Stanislav Engel, Susanne Neumann, Navneet Kaur, Vikramdeep Monga, Rahul Jain, John Northup^¶, and Marvin C. Gershengorn¹

From the Clinical Endocrinology Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892, the Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar-160 062, Punjab, India, and the ^¶Laboratory of Cellular Biology, NIDCD, National Institutes of Health, Bethesda, Maryland 20892

We show that several analogs of thyrotropin-releasing hormone (TRH) are more efficacious agonists at TRH receptors R1 and R2 than TRH itself. The apparent efficacies of the analogs were inversely related to their potencies and were independent of the nature of the modifications in TRH structure. In studies in intact cells, we showed that the differences in apparent efficacies were not due to differences in G-protein coupling, receptor desensitization, or recycling. Moreover, the differences in efficacies persisted in experiments using accessory protein-free membranes. We conclude that the efficacy differences of TRH analogs originated from the enhanced ability of TRH-R complexed to the low affinity agonists to directly activate G-protein(s), and not by a modulation of the activity of accessory proteins, and propose possible mechanisms for this phenomenon.

Received for publication, January 17, 2006 , and in revised form, March 10, 2006.

^* This research was supported by the Intramural Research Program of the NIDDK, National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: NIDDK/National Institutes of Health, 50 South Drive, Rm. 4134, Bethesda, MD 20892-8029. Tel.: 301-451-6305; Fax: 301-480-4214; E-mail: marving{at}intra.niddk.nih.gov.

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