Pituitary Adenylate Cyclase Activating Polypeptide PACAP

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PACAP was originally extracted from the pituitary gland in 1989 by Dr. Arimura and collaborators. Two forms of PACAP exist consisting of 27 and 38 amino acids, respectively, and PACAP, like VIP, belongs to the glucagon superfamily of peptides. In fact, PACAP

Pacap Peptide

Figure 4 Schematic representation of the PACAP gene and proPACAP. The first exon is non-encoding, exon 2 encodes the signal peptide, and exons 3-5 encode the proPACAP sequence. At the bottom of the figure are the amino acid sequences of PACAP27, PACAP38, and PRP (PACAP-related peptide). * indicates a C-terminal NH2 group.

Figure 4 Schematic representation of the PACAP gene and proPACAP. The first exon is non-encoding, exon 2 encodes the signal peptide, and exons 3-5 encode the proPACAP sequence. At the bottom of the figure are the amino acid sequences of PACAP27, PACAP38, and PRP (PACAP-related peptide). * indicates a C-terminal NH2 group.

shows 68% identity to VIP. The gene for PACAP is located on chromosome 18p11 and consists of five exons. The entire PACAP sequence is included in the fifth exon. Transcription and translation of the second exon yield a 24-residue signal peptide, whereas the fifth exon encodes the PACAP precursor, which is 152 residues long. PACAP38 is equivalent to proPA-CAP108 145 (Fig. 4). PACAP27 is then cleaved from PACAP38, consisting of its 27 N-terminal amino acids (PACAP381 27). In various tissues, including the pancreas, the main PACAP form is PACAP38. In addition, a PACAP-related peptide (PRP) is formed from proPACAP57 85. Although this peptide, like PACAP, is distributed in a variety of organs and its structure shows a 44% resemblance to PHM, its function is still not known.

Like VIP, PACAP is also distributed ubiquitously and occurs mainly in nerves in the central nervous system, the lungs, and the gastrointestinal tract. PA-CAP has been demonstrated to exert a multitude of effects in these organs, such as relaxation of smooth muscle cells and stimulation of secretion from the pituitary and adrenal glands. In the central nervous system, a neurotrophic action of the peptide has also been reported. The neuropeptide is located in islet nerve terminals and in pancreatic ganglia, and because it is released from the pancreas during electrical activation of the vagal nerves, it is thought to be mainly a parasympathetic neuropeptide. It has, however, also been reported that PACAP is a neurotrans-mitter in sensory nerves. Finally, in one study PACAP has also been reported to be expressed not only in pancreatic nerves but also in islet b cells, although this has not been confirmed in other studies.

Like parasympathetic nerve activation, PACAP potently stimulates the secretion of both insulin and glucagon, which has been demonstrated both in vivo and in vitro in a number of experimental conditions. Like VIP, PACAP stimulates insulin secretion in a glucose-dependent manner accompanied by increased action of adenylate cyclase with increased formation of cAMP and activation of PKA. PACAP also exerts, however, other signaling actions in insulin producing tissues, like an increase in the cytoplasmic concentrations of both Ca2+ and Na+ and a distal effect on the exocytosis machinery. It is possible that the potency of PACAP to stimulate insulin secretion, which exceeds that of VIP, is due to the diversity of signaling actions induced by PACAP in islet b cells.

The close relation between PACAP and VIP is evidenced by the structural similarity of the peptides and by the affinity of both peptides to the VPAC1 and VPAC2 receptors. However, the findings that PACAP is more potent in stimulating insulin secretion than VIP and that signaling pathways other than the cAMP PKA pathway also seem to be activated by PACAP suggest the existence of a third PACAP receptor, which is specific for PACAP. Such a receptor has also been cloned and named the PAC1 receptor, and it is, like the two VPAC receptors, of the seven transmembranous domain type and G-protein-cou-pled. The PAC1 receptor gene is located on chromosome 7p15-p14, and the receptor consists of 525 amino acids. The PAC1 receptor is further divided into eight subtypes, all resulting from alternative splicing. The function of this splicing is not known, although different affinities for various PACAP forms have been documented for the different splice variants. In pancreatic islets, the occurrence of PAC1 and VPAC2 receptors has been verified.

The functional relevance of the PACAP nerves for islet function has started to emerge. One study used a PACAP antagonist, the 22 C-terminally located residues in PACAP27, i.e., PACAP6 27, and administered it to mice. It was first demonstrated that the antagonist indeed is a PACAP antagonist, because insulin secretion stimulated by exogenously administered PA-CAP27 was inhibited by the antagonist. It was also found that the antagonist was without effect on the insulin response to exogenous VIP, suggesting that the antagonist is specific for PAC1 receptors. When this antagonist was administered to mice challenged with a gastric administration of glucose, the resulting insulin response was impaired. This suggests that PACAP is involved in the neural mediation of the insulin response to food intake. Similar results were also shown in a mouse model from which the PAC1 receptor had been deleted. The model was developed by Dr. Brabet and collaborators in Montpellier by genetic targeting, and a gastric challenge with glucose was found to display a reduced insulin response in these mice compared to wild-type controls. Furthermore, studies undertaken in isolated islets have demonstrated that specific PACAP antisera not only reduce the insulin response to PACAP but also reduce the insulin response to glucose alone. Because this was not observed in islets that had been cultured for 48 hr and therefore were devoid of any remaining PACAP in surviving islet nerve terminals, it is likely that the insulinotropic response to glucose is dependent on release of PACAP and intact PACAP receptors. Similar results with reduced glucose-stimulated insulin secretion were also reported in the PAC1-receptor-deleted mouse model. Hence, PACAP seems to be an islet neuropeptide of importance for islet function, notably after activation by glucose and postprandially.

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