This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tao, Y.-X. Articles by Segaloff, D. L. Search for Related Content PubMed PubMed Citation Articles by Tao, Y.-X. Articles by Segaloff, D. L.

Functional Characterization of Melanocortin-3 Receptor Variants Identify a Loss-of-Function Mutation Involving an Amino Acid Critical for G Protein-Coupled Receptor Activation

Department of Physiology and Biophysics, The University of Iowa Carver College of Medicine, Iowa City, Iowa 52242

Address all correspondence and requests for reprints to: Ya-Xiong Tao, Ph.D., Department of Physiology and Biophysics, 5-471 Bowen Science Building, The University of Iowa Carver College of Medicine, Iowa City, Iowa 52242. E-mail: ya-xiong-tao{at}uiowa.edu.

Although melanocortin-4 receptor mutations are the cause of the most common monogenic form of obesity, the involvement of the melanocortin-3 receptor (MC3R) in the pathogenesis of obesity is unknown. Earlier studies failed to identify any mutations in obese patients except for the identification of two variants (K6T and I81V) that likely represent polymorphisms. However, a potential mutation (I183N) was recently reported from patients having high-fat contents. We report here the functional characterization of these variants. We show that K6T and I81V have ligand binding and signaling properties similar to wild-type (wt) MC3R, indicating that they are indeed polymorphisms. However, the other variant, I183N, completely lacks signaling in response to agonist stimulation, although it binds ligand with normal affinity and with only slightly decreased capacity. Coexpression of the wt and I183N MC3Rs showed that I183N does not exert dominant-negative activity on wt MC3R. These results provide supporting evidence for the hypothesis proposed in the original case report that MC3R mutation might be a genetic factor that confers susceptibility to obesity, likely due to haploinsufficiency. Further mutations at I183 revealed a discrete requirement for I183 in agonist-induced MC3R activation. The corresponding residue is also important for agonist-induced human melanocortin-4 receptor and lutropin receptor activation. In summary, we identify a residue that is critical for activation of G protein-coupled receptors.

This work was supported by a Beginning-Grant-in-Aid (0265236Z) from the American Heart Association Heartland Affiliate (to Y.-X.T.) and National Institutes of Health Grant HD22196 (to D.L.S.).

Abbreviations: CG, Chorionic gonadotropin; GPCR, G proteincoupled receptor; h, human; LHR, human lutropin receptor; MCR, melanocortin receptor; MSH, melanocyte stimulating hormone; NDP-MSH, [Nle⁴,D-Phe⁷]-MSH; NIDDM, non-insulin-dependent diabetes mellitus; POMC, proopiomelanocortin; TM, transmembrane; wt, wild-type.

This article has been cited by other articles:

				M. A. Calton, B. A. Ersoy, S. Zhang, J. P. Kane, M. J. Malloy, C. R. Pullinger, Y. Bromberg, L. A. Pennacchio, R. Dent, R. McPherson, et al. Association of functionally significant Melanocortin-4 but not Melanocortin-3 receptor mutations with severe adult obesity in a large North American case-control study Hum. Mol. Genet., March 15, 2009; 18(6): 1140 - 1147. [Abstract] [Full Text] [PDF]

				Z.-C. Fan, J. L Sartin, and Y.-X. Tao Molecular cloning and pharmacological characterization of porcine melanocortin-3 receptor J. Endocrinol., January 1, 2008; 196(1): 139 - 148. [Abstract] [Full Text] [PDF]

				Y. Seng Lee, L. Kok Seng Poh, B. Lay Kee Kek, and K. Yin Loke The Role of Melanocortin 3 Receptor Gene in Childhood Obesity Diabetes, October 1, 2007; 56(10): 2622 - 2630. [Abstract] [Full Text] [PDF]

				Y.-X. Tao and D. L. Segaloff Functional Analyses of Melanocortin-4 Receptor Mutations Identified from Patients with Binge Eating Disorder and Nonobese or Obese Subjects J. Clin. Endocrinol. Metab., October 1, 2005; 90(10): 5632 - 5638. [Abstract] [Full Text] [PDF]

				N. Feng, S. F. Young, G. Aguilera, E. Puricelli, D. C. Adler-Wailes, N. G. Sebring, and J. A. Yanovski Co-occurrence of Two Partially Inactivating Polymorphisms of MC3R Is Associated With Pediatric-Onset Obesity Diabetes, September 1, 2005; 54(9): 2663 - 2667. [Abstract] [Full Text] [PDF]