Dual effects of PACAP on guinea pig gallbladder muscle via PACAP-preferring and VIP/PACAP-preferring receptors

Abstract

The aims of this study were to determine the effect and mechanism of action of pituitary adenylate cyclase-activating peptide (PACAP) on gallbladder muscle. Guinea pig gallbladder muscle strips were studied isometrically. In noncontracted muscle strips, PACAP-27 and PACAP-38 caused dose-dependent contractions, whereas vasoactive intestinal peptide (VIP) caused dose-dependent relaxation. PACAP-27 contractions were resistant to tetrodotoxin, atropine, and the substance P receptor antagonist [D-Arg1,D-Trp7,9,Leu11]substance P (Spantide) but were inhibited by the selective PACAP receptor antagonist PACAP-(6-38) and slightly increased with the VIP receptor antagonist [4-chloro-D-Phe6,Leu17]VIP. In cholecystokinin-precontracted muscle strips, both VIP and PACAP caused relaxations. This relaxant effect of PACAP-27 was inhibited by PACAP-(6-38) and [4-chloro-D-Phe6,Leu17]VIP, but not by tetrodotoxin. These studies suggest that PACAP has dual excitatory and inhibitory effects on guinea pig gallbladder muscle. The contractile effect of PACAP is a direct action on muscle through PACAP-preferring receptors. The relaxant effect of PACAP is seen in precontracted muscle strips and mediated through VIP/ PACAP-preferring receptors.

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

“…In agreement with previous studies (15,23,24), PACAP induced contraction of the muscle strips that was followed by relaxation, whereas VIP consistently induced relaxation (Figs. 1 and 2).…”

“…PACAP and VIP are coexpressed in nerve fibers and neurons in the ganglia of the guinea pig gallbladder (7). Although both peptides act primarily as inhibitory transmitters on most gastrointestinal and vascular smooth muscle cells (5,6,12), their actions on the gallbladder are opposite; VIP relaxes the gallbladder, whereas PACAP induces the contraction both in vivo (9) and in vitro (15,23,24).Three receptor subtypes that recognize PACAP and VIP have been identified (4,22), and all belong to the group of seven transmembrane G protein-coupled receptors. The PACAP-specific (PAC 1 ) receptor has a much higher affinity for PACAP than VIP, whereas the classical VIP (VPAC 1 ) receptor and VPAC 2 receptor exhibit similar affinities for PACAP and VIP.…”

“…PACAP and VIP are coexpressed in nerve fibers and neurons in the ganglia of the guinea pig gallbladder (7). Although both peptides act primarily as inhibitory transmitters on most gastrointestinal and vascular smooth muscle cells (5,6,12), their actions on the gallbladder are opposite; VIP relaxes the gallbladder, whereas PACAP induces the contraction both in vivo (9) and in vitro (15,23,24).…”

Effect of GHRH and peptides from the vasoactive intestinal peptide family on cAMP production of human cancer cell lines in vitro

“…These peptides show extensive homologies in amino acid sequences, and overlapping functions (Ciampani et al 1992, Inagaki et al 1996, Vertongen et al 1996, Parkman et al 1997a. Potent VIP agonists and antagonists also show extensive structural homology with GHRH(1-29) (Gourlet et al 1997a, b).…”

“…All the receptors that can bind these hormones with considerable cross-activity are members of the seven transmembranespanning receptor superfamily (Laburthe et al 1996). These peptides, especially GHRH, VIP and PACAP, exhibit similar effect on several organs, including testis (Csaba et al 1997), gall bladder (Parkman et al 1997a), pyloric muscle (Parkman et al 1997b), or pancreas (Inagaki et al 1996), apparently mediated by common receptors. Various findings indicate that receptors of peptide hormones belonging to the GHRH-VIP family are present on colon (Ogasawara et al 1997), pancreatic (Schafer et al 1996), lung (Davidson et al 1996), prostate (Gkonos et al 1996) and breast (Zia et al 1996) cancers and mesenchymal (Reubi et al 1996) and neural (Lelievre et al 1996, Vertongen et al 1996 tumors, and are involved in the proliferation of these tumors.…”