Pituitary Adenylate Cyclase Activating Polypeptides (PACAP, ADCYAP1: adenylate cyclase-activating polypeptide 1), is a neuropeptide in pancreatic islets, where it has been suggested as a parasympathetic and sensory neurotransmitter.
Discovery
In 1989, Arimura et al., isolated novel PACAP, hypophysiotropic neuropeptides, the group of Arimura has screened fractions from an extract of 4300 ovine hypothalamus by monitoring their stimulatory effect on adenylyl cyclase activity in cultured rat anterior pituitary cells. Using this approach, they have isolated in pure form a peptide, found to markedly increase cAMP formation, that they termed pituitary adenylate cyclase-activating polypeptide 1.
PACAP Fragments
The two forms of pituitary adenylate cyclase-activating Polypeptide are PACAP-27 and PACAP-38. PACAP38 (4.5 kDa), but was later found to also exist in a COOH-terminally truncated 27–amino acid long-form equivalent to PACAP38 (1–27) and thus called PACAP27 (3.0 kDa). In addition, PACAP27 is amidated at its COOH-terminal end. In all tissues examined, PACAP38 is the predominant form of PACAP. The peptide is structurally related to VIP and is therefore a member of the glucagon/VIP family of peptides comprising secretin, helodermin, helospectin, and GLP-1. In fact, PACAP27 displays 68% identity with the full length of VIP 2.
Structural Characteristics
Conformational analysis of PACAP27 by two-dimensional NMR and circular dichroism spectroscopy has shown an initial disordered N-terminus sequence of eight amino acid residues followed by a region, from amino acid residues 9 to 24, that consists of four distinct domains 3. The first domain, encompassing residues 9 to 12, forms a b-turn-like conformation whereas the three others are composed of distinct helical regions that extend from residues 12 to 14, 15 to 20, and 22 to 24, respectively. The conformation of PACAP38 mirrors that of PACAP27 in its N-terminal region whereas the C-terminal segment exhibits a short helix attached by a flexible hinge to the 1–27 region 4.
The three-dimensional structure of PACAP exhibits substantial similarities with those of other members of the VIP/glucagon family 4. In particular, both PACAP27 and VIP possess two helices separated by a disordered region, but the position of the first a-helix of PACAP27 is shifted by two residues toward the C-terminus, and the conformation of the second helix of PACAP27 is closer to an a-helix than that of VIP. These minor conformational differences between PACAP27 and VIP may contribute to the selectivity of the peptides for their receptors 3.
Mode of Action
The wide distribution of PACAP and its receptors suggests that the peptide may exert pleiotropic physiological functions. The PACAP receptor is G protein-coupled with seven transmembrane domains and also belongs to the VIP receptor family. The biological effects of PACAP are mediated through three distinct receptor subtypes which exhibit differential affinities for PACAP and VIP. The PAC1 receptor, which shows high selectivity for PACAP, is coupled to several transduction systems. In contrast, VPAC1 and VPAC2, which bind with the same affinity PACAP and VIP, are mainly coupled to the adenylyl cyclase pathway. In vivo and in vitro studies have shown that PACAP exerts multiple activities as a hormone, neurohormone, neurotransmitter or trophic factor5.
Functions
Action of pituitary adenylate cyclase-activating polypeptide and vasoactive intestinal polypeptide on the rat vascular system: effects on blood pressure and receptor binding: The administration of bolus doses of PACAP 38 and its 27 amino acid N-terminal fragment (PACAP 27) caused a rapid but transient dose-dependent hypotensive effect in the anaesthetized rat. The amplitude and duration of the response obtained by PACAP 38 was comparable with VIP whereas PACAP 27 was three times less potent than VIP. Furthermore, radioreceptor binding studies demonstrated that 125I-labelled PACAP 27 and 125I-labelled VIP bound to membranes prepared from blood vessels. Both PACAP 27 and VIP were capable of displacing the other from these binding sites6.
Pituitary adenylate cyclase-activating polypeptide is associated with schizophrenia: PACAP, a neuropeptide with neurotransmission modulating activity, is a promising schizophrenia candidate gene. There is evidence that genetic variants of the genes encoding PACAP and its receptor, PAC1, are associated with schizophrenia. The effects of the associated polymorphism in the PACAP gene is studied on neurobiological traits related to risk for schizophrenia. This allele of the PACAP gene, which is overrepresented in schizophrenia patients, was associated with reduced hippocampal volume and poorer memory performance. Abnormal behaviors in PACAP knockout mice, including elevated locomotor activity and deficits in prepulse inhibition of the startle response, were reversed by treatment with an atypical antipsychotic, risperidone. These convergent data suggest that alterations in PACAP signaling might contribute to the pathogenesis of schizophrenia7.
References
1.Miyata A, Arimura A, Dahl RR, Minamino N, Uehara A, Jiang L, Culler MD, Coy DH (1989). Isolation of a novel 38 residue-hypothalamic polypeptide which stimulates adenylate cyclase in pituitary cells. Biochem Biophys Re. Commun., 164:567-574.
2.Miyata A, Jiang L, Dahl RR, Kitada C, Kubo K, Fujino M, Minamino N, Arimura A (1990). Isolation of a neuropeptide corresponding to the N-terminal 27 residues of the pituitary adenylate cyclase activating polypeptide with 38 residues (PACAP38). Biochem Biophys Res Commun., 170:643-648.
3.Inooka H, Endo S, Kitada C, Mizuta E and Fujino M (1992) Pituitary adenylate cyclase-activating polypeptide (PACAP) with 27 residues. Conformation determined by 1:H NMR and CD spectroscopies and distance geometry in 25% methanol solution. Int. J. Pept. Protein. Res., 40:456-464.
4.Wray V, Kokoschke C, Nokihara K and Naruse S (1993) Solution structure of pituitary adenylate cyclase-activating polypeptide by nuclear magnetic resonance spectroscopy. Biochemistry, 32:5832-5841.
5.Gonzalez BJ, Basille M, Vaudry D, Fournier A, Vaudry H (1998). Pituitary adenylate cyclase-activating polypeptide. Ann Endocrinol., 59(5):364-405.
6.KA Nandha, MA Benito-Orfila, DM Smith, MA Ghatei and SR Bloom (1991). Action of pituitary adenylate cyclase-activating polypeptide and vasoactive intestinal polypeptide on the rat vascular system: effects on blood pressure and receptor binding. Journal of Endocrinology, 129:69-73.
7.Hashimoto R, Hashimoto H, Shintani N, Chiba S, Hattori S, Okada T, Nakajima M, Tanaka K, Kawagishi N, Nemoto K, Mori T, Ohnishi T, Noguchi H, Hori H, Suzuki T, Iwata N, Ozaki N, Nakabayashi T, Saitoh O, Kosuga A, Tatsumi M, Kamijima K, Weinberger DR, Kunugi H, Baba A (2007). Pituitary adenylate cyclase-activating polypeptide is associated with schizophrenia. Mol Psychiatry., 12(11):1026-1032.
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