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