The Origin and Function of the Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP)/Glucagon Superfamily*

Sherwood, Nancy M.; Krueckl, Sandra L.; McRory, John E.

doi:10.1210/edrv.21.6.0414

Cited by 350 publications

(329 citation statements)

References 587 publications

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“…(iii) The UII receptor UTR shares high sequence identity with the somatostatin receptors (45), and the UTR gene is physically linked with the gene encoding one of the somatostatin receptors, SST 3 , at 17q23, suggesting that these two receptors arose by local duplication. These observations provide strong evidence for co-evolution of the somatostatin͞UII family of peptides and their cognate receptors SSTs͞UTR, consistent with the notion that related G protein-coupled receptors, such as NPY receptors, VIP͞PACAP receptors, and opiate receptors, are usually activated by paralogous peptides (46)(47)(48).…”

Section: Discussionsupporting

confidence: 84%

Comparative genomics provides evidence for close evolutionary relationships between the urotensin II and somatostatin gene families

Tostivint

Joly

Lihrmann

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Although urotensin II (UII) and somatostatin 1 (SS1) exhibit some structural similarities, their precursors do not show any appreciable sequence identity and, thus, it is widely accepted that the UII and SS1 genes do not derive from a common ancestral gene. The recent characterization of novel isoforms of these two peptides, namely urotensin II-related peptide (URP) and somatostatin 2 (SS2)͞ cortistatin (CST), provides new opportunity to revisit the phylogenetic relationships of UII and SS1 using a comparative genomics approach. In the present study, by radiation hybrid mapping and in silico sequence analysis, we have determined the chromosomal localization of the genes encoding UII-and somatostatin-related peptides in several vertebrate species, including human, chicken, and zebrafish. In most of the species investigated, the UII and URP genes are closely linked to the SS2͞CST and SS1 genes, respectively. We also found that the UII-SS2͞CST locus and the URP͞SS1 locus are paralogous. Taken together, these data indicate that the UII and URP genes, on the one hand, and the SS1 and SS2͞CST genes, on the other hand, arose through a segmental duplication of two ancestral genes that were already physically linked to each other. Our results also suggest that these two genes arose themselves through a tandem duplication of a single ancestral gene. It thus appears that the genes encoding UII-and somatostatinrelated peptides belong to the same superfamily.duplication ͉ multigenic family ͉ neuropeptides ͉ radiation hybrid mapping

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Section: Discussionsupporting

confidence: 84%

Comparative genomics provides evidence for close evolutionary relationships between the urotensin II and somatostatin gene families

Tostivint

Joly

Lihrmann

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…The neuropeptide vasoactive intestinal peptide (VIP) 1 is present in both central and peripheral nervous systems as well as in immune cells (1). It controls a large array of biological functions in the brain and peripheral organs (1) and was shown recently to exert potent anti-inflammatory actions (2).…”

mentioning

confidence: 99%

“…It controls a large array of biological functions in the brain and peripheral organs (1) and was shown recently to exert potent anti-inflammatory actions (2). The two cloned VIP receptors also bind with high affinity another neuropeptide, the pituitary adenylyl cyclase-activating peptide, and have been named VPAC 2 receptors thereby (3).…”

mentioning

confidence: 99%

“…This was done by substituting para-benzoyl-L-Phe (Bpa) for phenylalanine 6. This site of incorporation was selected for several reasons: (i) Phe 6 is important for the biological activity of VIP (9) and is strictly conserved in all natural hormones structurally related to VIP (1). (ii) The substitution of Bpa for phenylalanine keeps an aromatic residue, and we expected that, even though Phe 6 is important for biological activity, the [Bpa 6 ]-VIP probe should keep reasonable affinity for the receptor.…”

mentioning

confidence: 99%

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Diffuse Pharmacophoric Domains of Vasoactive Intestinal Peptide (VIP) and Further Insights into the Interaction of VIP with the N-terminal Ectodomain of Human VPAC1 Receptor by Photoaffinity Labeling with [Bpa6]-VIP

Tan

Couvineau

Laburthe

2004

Journal of Biological Chemistry

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The neuropeptide vasoactive intestinal peptide (VIP) 1 is present in both central and peripheral nervous systems as well as in immune cells (1). It controls a large array of biological functions in the brain and peripheral organs (1) and was shown recently to exert potent anti-inflammatory actions (2). The two cloned VIP receptors also bind with high affinity another neuropeptide, the pituitary adenylyl cyclase-activating peptide, and have been named VPAC 2 receptors thereby (3). They are class II G protein-coupled receptor-like receptors for all peptides structurally related to VIP and also receptors for parathyroid hormone, calcitonin, and corticotropin-releasing factor (3).The VPAC1 receptor is prototypic of class II G protein-coupled receptors and has been extensively studied by molecular biology techniques including site-directed mutagenesis and molecular chimerism (for review see Ref.3). These studies made it possible to delineate the receptor domains involved in high affinity VIP binding (3), selectivity toward some natural peptide agonists (4, 5) and also activation of adenylyl cyclase (6). With respect to VIP binding, it appeared that the N-terminal ectodomain of the receptor plays a crucial role, although it is not sufficient to ensure high affinity (3). A three-dimensional model of the N-terminal ectodomain of the hVPAC1 receptor has been developed suggesting the existence of a VIP-binding groove within this domain (7). Despite these extensive studies of the structure-function relationship of hVPAC1 receptor, the physical sites of interaction between VIP and its receptors had remained elusive until recent photoaffinity showing labeling experiments that the side chain of position 22 of VIP is in direct contact with one edge of the putative binding groove in the N-terminal ectodomain (8).It is well known that VIP has diffuse pharmacophoric domains, with the amino acid residues important for biological activity being distributed along the whole 28-amino acid peptide chain (9). In this context, we further explored the contact sites between VIP and the hVPAC1 receptor by incorporating a photoactivable benzophenone group on the side chain at position 6 of VIP. This was done by substituting para-benzoyl-L-Phe (Bpa) for phenylalanine 6. This site of incorporation was selected for several reasons: (i) Phe 6 is important for the biological activity of VIP (9) and is strictly conserved in all natural hormones structurally related to VIP (1). (ii) The substitution of Bpa for phenylalanine keeps an aromatic residue, and we expected that, even though Phe 6 is important for biological activity, the [Bpa 6 ]-VIP probe should keep reasonable affinity for the receptor. (iii) Position 6 and the previously explored position 22 (8) are at the two ends of the central ␣-helical domain of VIP (9, 10). We report here that the amino acid in

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“…Pituitary adenylate cyclase-activating polypeptide (PACAP), 1 originally isolated from ovine hypothalamus (1) by following pituitary adenylate cyclase activation, belongs to the secretin/glucagon/vasoactive intestinal peptide (VIP) family of peptides (2). These peptides are expressed as part of larger proteins that are processed by proteolysis followed by Cterminal amidation to generate the mature amidated peptides (Fig.…”

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confidence: 99%

Generation of Highly Selective VPAC2 Receptor Agonists by High Throughput Mutagenesis of Vasoactive Intestinal Peptide and Pituitary Adenylate Cyclase-activating Peptide

Yung¹,

Cruz

Hamren³

et al. 2003

Journal of Biological Chemistry

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Pituitaryadenylate cyclase-activating peptide (PACAP) has a specific receptor PAC1 and shares two receptors VPAC1 and VPAC2 with vasoactive intestinal peptide (VIP). VPAC2 activation enhances glucose-induced insulin release while VPAC1 activation elevates glucose output. To generate a large pool of VPAC2 selective agonists for the treatment of type 2 diabetes, structure-activity relationship studies were performed on PACAP, VIP, and a VPAC2 selective VIP analog. Chemical modifications on this analog that prevent recombinant expression were sequentially removed to show that a recombinant peptide would retain VPAC2 selectivity. An efficient recombinant expression system was then developed to produce and screen hundreds of mutant peptides. The 11 mutations found on the VIP analog were systematically replaced with VIP or PACAP sequences. Three of these mutations, V19A, L27K, and N28K, were sufficient to provide most of the VPAC2 selectivity. C-terminal extension with the KRY sequence from PACAP38 led to potent VPAC2 agonists with improved selectivity (100 -1000-fold). Saturation mutagenesis at positions 19, 27, 29, and 30 of VIP and chargescanning mutagenesis of PACAP27 generated additional VPAC2 selective agonists. We have generated the first set of recombinant VPAC2 selective agonists described, which exhibit activity profiles that suggest therapeutic utility in the treatment of diabetes.Pituitary adenylate cyclase-activating polypeptide (PACAP), 1 originally isolated from ovine hypothalamus (1) by following pituitary adenylate cyclase activation, belongs to the secretin/glucagon/vasoactive intestinal peptide (VIP) family of peptides (2). These peptides are expressed as part of larger proteins that are processed by proteolysis followed by Cterminal amidation to generate the mature amidated peptides (Fig. 1). PACAP exists as a 38-residue form (PACAP38), and as a shorter form corresponding to the N-terminal 27 amino acids of PACAP38 (PACAP27). Both forms of PACAP bind to and activate the G-protein-coupled receptors PAC1, VPAC1, and VPAC2, whereas the related 28-mer peptide VIP only recognizes VPAC1 and VPAC2 (3). Activation of multiple receptors by PACAP or VIP has broad physiological effects on nervous, endocrine, cardiovascular, reproductive, muscular, and immune systems (4). Thus, clinical applications will require selective activation of a particular receptor to minimize potential side effects mediated by the other receptors. For example, we have previously demonstrated that VPAC2 activation induces glucose-dependent insulin secretion without the undesired side effects mediated by VPAC1 such as watery diarrhea (5). Therefore, to provide a potential therapy for type 2 diabetes, VPAC2 selectivity is an absolute requirement.We sought to identify key determinants of VPAC2 selectivity and generate a peptide with the minimum number of mutations. However, structure-function relationship studies on VIP and PACAP (6 -15) have been restricted by the number of peptides that can be tested due to limitations of peptide synth...

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The Origin and Function of the Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP)/Glucagon Superfamily*

Cited by 350 publications

References 587 publications

Comparative genomics provides evidence for close evolutionary relationships between the urotensin II and somatostatin gene families

Comparative genomics provides evidence for close evolutionary relationships between the urotensin II and somatostatin gene families

Diffuse Pharmacophoric Domains of Vasoactive Intestinal Peptide (VIP) and Further Insights into the Interaction of VIP with the N-terminal Ectodomain of Human VPAC1 Receptor by Photoaffinity Labeling with [Bpa6]-VIP

Generation of Highly Selective VPAC2 Receptor Agonists by High Throughput Mutagenesis of Vasoactive Intestinal Peptide and Pituitary Adenylate Cyclase-activating Peptide

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