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Molecular Pharmacology

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Research ArticleArticle

Vasoactive Intestinal Polypeptide and Pituitary Adenylate Cyclase-Activating Polypeptide Receptor Chimeras Reveal Domains That Determine Specificity of Vasoactive Intestinal Polypeptide Binding and Activation

Hitoshi Hashimoto, Nobuya Ogawa, Nami Hagihara, Kyohei Yamamoto, Kumiko Imanishi, Hiroyuki Nogi, Akiko Nishino, Takashi Fujita, Toshio Matsuda, Shigekazu Nagata and Akemichi Baba
Molecular Pharmacology July 1997, 52 (1) 128-135; DOI: https://doi.org/10.1124/mol.52.1.128
Hitoshi Hashimoto
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Nobuya Ogawa
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Nami Hagihara
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Kyohei Yamamoto
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Kumiko Imanishi
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Hiroyuki Nogi
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Akiko Nishino
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Takashi Fujita
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Toshio Matsuda
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Shigekazu Nagata
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Akemichi Baba
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Abstract

Vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) receptors are closely related G protein-coupled receptors with seven-transmembrane domains. The VIP receptor can bind both VIP and PACAP with high affinity, whereas the PACAP receptor binds only PACAP with high affinity. To elucidate the structural domains involved in a selectivity for VIP binding and the subsequent receptor activation, a series of chimeric receptors between the VIP and PACAP receptors was constructed, expressed in COS-7 cells, and analyzed for ligand binding and cAMP generation. All chimeric constructs bound PACAP with high affinity and subsequently activated cAMP generation similarly to the wild-type receptors. In contrast, profound differences were observed in the potencies of VIP for competition of 125I-labeled PACAP binding to both wild-type receptors and the chimeric receptors. The cAMP responses of these receptors generally correlated with the ability of VIP to compete for PACAP radioligand binding with the exceptions for some particular chimeras. In this report we demonstrate that several domains, including the amino-terminal extracellular domain, the transmembrane domains I and II, and the first extracellular loop of the VIP receptor, are important for the selectivity for VIP binding and responsiveness to VIP. We further show that the third extracellular loop and its proximal domains of the VIP receptor appear to be involved in the VIP recognition, especially the receptor activation process. On the other hand, the direct binding experiments of the VIP radioligand demonstrated that both wild-type receptors and all chimeric receptors have a high affinity binding site for VIP, although this high affinity VIP binding resulted in a biological response only in the VIP receptor or VIP receptor-like chimeras. This suggests that there is a nonbiologically relevant high affinity VIP-binding site within the rat PACAP receptor.

Footnotes

    • Received August 16, 1996.
    • Accepted April 11, 1997.
  • Send reprint requests to: Dr. Akemichi Baba, Faculty of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita Osaka 565, Japan. E-mail: baba{at}phs.osaka-u.ac.jp

  • This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan, and by grants from Uehara Memorial Foundation and Taisho Pharmaceutical.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 52 (1)
Molecular Pharmacology
Vol. 52, Issue 1
1 Jul 1997
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Research ArticleArticle

Vasoactive Intestinal Polypeptide and Pituitary Adenylate Cyclase-Activating Polypeptide Receptor Chimeras Reveal Domains That Determine Specificity of Vasoactive Intestinal Polypeptide Binding and Activation

Hitoshi Hashimoto, Nobuya Ogawa, Nami Hagihara, Kyohei Yamamoto, Kumiko Imanishi, Hiroyuki Nogi, Akiko Nishino, Takashi Fujita, Toshio Matsuda, Shigekazu Nagata and Akemichi Baba
Molecular Pharmacology July 1, 1997, 52 (1) 128-135; DOI: https://doi.org/10.1124/mol.52.1.128

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Research ArticleArticle

Vasoactive Intestinal Polypeptide and Pituitary Adenylate Cyclase-Activating Polypeptide Receptor Chimeras Reveal Domains That Determine Specificity of Vasoactive Intestinal Polypeptide Binding and Activation

Hitoshi Hashimoto, Nobuya Ogawa, Nami Hagihara, Kyohei Yamamoto, Kumiko Imanishi, Hiroyuki Nogi, Akiko Nishino, Takashi Fujita, Toshio Matsuda, Shigekazu Nagata and Akemichi Baba
Molecular Pharmacology July 1, 1997, 52 (1) 128-135; DOI: https://doi.org/10.1124/mol.52.1.128
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