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J. Biol. Chem., Vol. 279, Issue 52, 54445-54453, December 24, 2004

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Identification of Amino Acid Residues That Direct Differential Ligand Selectivity of Mammalian and Nonmammalian V1a Type Receptors for Arginine Vasopressin and Vasotocin

INSIGHTS INTO MOLECULAR COEVOLUTION OF V1a TYPE RECEPTORS AND THEIR LIGANDS^*

Sujata Acharjee, Jean-Luc Do-Rego, Da Young Oh, Ryun Sup Ahn, Han Choe¶, Hubert Vaudry, Kyungjin Kim||, Jae Young Seong**, and Hyuk Bang Kwon

From the Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea, the European Institute for Peptide Research (IFRMP 23), Laboratory of Cellular and Molecular Neuroendocrinology, INSERM U413, University of Rouen, 76821 Mont-Saint-Aignan, France, the ^¶Department of Physiology, Ulsan University College of Medicine, Songpagoo Poongnapdong 388-1, Seoul 138-736, Republic of Korea, and the ^||School of Biological Sciences, Seoul National University, Seoul 151-742, Republic of Korea

Arginine vasotocin (VT) is the ortholog in all nonmammalian vertebrates of arginine vasopressin (AVP) in mammals. We have previously cloned an amphibian V1atype vasotocin receptor (VT1R) that exhibited higher sensitivity for VT than AVP, while the mammalian V1a type receptor (V1aR) responded better to AVP than VT. In the present study, we identified the amino acid residues that confer differential ligand selectivity for AVP and VT between rat V1aR and bullfrog VT1R (bfVT1R). A chimeric rat V1aR having transmembrane domain (TMD) VI to the carboxyl-terminal tail (C-tail) of bfVT1R showed a reverse ligand preference for AVP and VT, whereas a chimeric VT1R with TMD VI to the C-tail of rat V1aR showed a great increase in sensitivity for AVP. A single mutation (Ile^315(6.53) to Thr) in TMD VI of V1aR increased the sensitivity for VT, while a single mutation (Phe^313(6.51) to Tyr or Pro^334(7.33) to Thr) reduced sensitivity toward AVP. Interestingly the triple mutation (Phe^313(6.51) to Tyr, Ile^6.53 to Thr, and Pro^7.33 to Thr) of V1aR increased sensitivity to VT but greatly reduced sensitivity to AVP, behaving like bfVT1R. Further, like V1aR, a double mutant (Tyr^306(6.51) to Phe and Thr^327(7.33) to Pro) of bfVT1R showed an increased sensitivity to AVP. These results suggest that Phe/Tyr^6.51, Ile/Thr^6.53, and Pro/Thr^7.33 are responsible for the differential ligand selectivity between rat V1aR and bfVT1R. This information regarding the molecular interaction of VT/AVP with their receptors may have important implications for the development of novel AVP analogs.

Received for publication, August 4, 2004 , and in revised form, September 8, 2004.

^* This work was supported by Korea Research Foundation Grant No. KRF-2002-070-C007 (to H. B. K.), by Brain Research Center of the 21st Century Frontier Research Program Grant M103KV010004 03K2201 00410 (to J. Y. S.), and by the Science and Technology Amicable Research exchange program (to H. B. K., J. Y. S., and H. V.). 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.

^** To whom correspondence may be addressed. Tel.: 82-62-530-1399; Fax: 82-62-530-0500; E-mail: jyseong{at}jnu.ac.kr. To whom correspondence may be addressed. Tel.: 82-62--530-3391; Fax: 82-62-530-0500; E-mail: kwonhb{at}jnu.ac.kr.

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