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Am J Physiol Gastrointest Liver Physiol 292: G76-G83, 2007. First published August 10, 2006; doi:10.1152/ajpgi.00279.2006
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NEUROREGULATION AND MOTILITY

Identification of key residues that cause differential gallbladder response to PACAP and VIP in the guinea pig

Muxin Wei,1,2 Kotoyo Fujiki,3,4 Eiji Ando,5 Sumin Zhang,3,4 Tsuyoshi Ozaki,4 Hiroshi Ishiguro,3 Takaharu Kondo,3 Kiyoshi Nokihara,5 Victor Wray,6 and Satoru Naruse2

1The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; 2Internal Medicine and 3Human Nutrition, Nagoya University Graduate School of Medicine, Nagoya, Japan; 4National Institute of Physiological Sciences, Okazaki, Japan; 5Biotechnology Instruments Department, Shimadzu Corporation, Kyoto, Japan; and 6Department of Structural Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany

Submitted 22 June 2006 ; accepted in final form 2 August 2006

Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP) have opposite actions on the gallbladder; PACAP induces contraction, whereas VIP induces relaxation. Here, we have attempted to identify key residues responsible for their interactions with PACAP (PAC1) and VIP (VPAC) receptors in the guinea pig gallbladder. We synthesized PACAP-27/VIP hybrid peptides and compared their actions on isolated guinea pig gallbladder smooth muscle strips using isotonic transducers. [Ala4]- and [Val5]PACAP-27 were more potent than PACAP-27 in stimulating the gallbladder. In contrast, [Ala4, Val5]- and [Ala4, Val5, Asn9]PACAP-27 induced relaxation similarly to VIP. [Asn9]-, [Thr11]-, or [Leu13]PACAP-27 had 20–70% contractile activity of PACAP-27, whereas [Asn24,Ser25,Ile26]PACAP-27 showed no change in the activity. All VIP analogs, including [Gly4,Ile5,Ser9]VIP, induced relaxation. In the presence of a PAC1 receptor antagonist, PACAP(6–38), the contractile response to PACAP-27 was inhibited and relaxation became evident. RT-PCR analysis revealed abundant expressions of PAC1 receptor, "hop" splice variant, and VPAC1 and VPAC2 receptor mRNAs in the guinea pig gallbladder. In conclusion, PACAP-27 induces contraction of the gallbladder via PAC1/hop receptors. Gly4 and Ile5 are the key NH2-terminal residues of PACAP-27 that distinguish PAC1/hop receptors from VPAC1/VPAC2 receptors. However, both the NH2-terminal and {alpha}-helical regions of PACAP-27 are required for initiating gallbladder contraction.

PAC1 receptor; VPAC1 receptor; VPAC2 receptor; splice variant


Address for reprint requests and other correspondence: S. Naruse, Internal Medicine, Nagoya Univ. Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan (e-mail: snaruse{at}med.nagoya-u.ac.jp)






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