Effects of neuropeptides of the secretin/VIP/PACAP family on cyclic AMP formation in the chick hypothalamus and cerebral cortex

Six neuropeptides: short and long form of the pituitary adenylate cyclase activating polypeptide (PACAP), i.e. PACAP27 and PACAP38, vasoactive intestinal peptide (VIP), peptide histidine-isoleucine (PHI), secretin and glucagon, members of the secretin/VIP/PACAP superfamily ofpolypeptides, were tested for their ability to stimulate cyclic AMP formation in [3H]adenine-prelabeled slices of the chick hypothalamus and cerebral cortex. Of the tested peptides, only PACAP evoked pronounced and significant responses in the two analyzed brain structures. Although magnitude of the responses varied in different experiments, the effects of both forms of PACAP were usually larger in the cerebral cortex than in the hypothalamus. Glucagon, PHI (both used at concentrations 0.01-1 microM) and VIP (0.1-3 microM) induced concentration-dependent yet comparatively small effects that did not reach statistical significance, while secretin (0.1-3 microM) had no effect.     

Effect of vasoactive intestinal peptide (VIP)-related peptides on cholinergic neurogenic and direct mucus secretion in ferret trachea in vitro

1 We investigated whether vasoactive intestinal peptide (VIP) and its related peptides, pituitary adenylate cyclase activating peptide (PACAP) and secretin, regulate cholinergic neural mucus secretion in ferret trachea in vitro, using 35SO4 as a mucus marker. We also studied the interaction between VIP and secretin on cholinergic mucus output. 2 VIP (1 and 10 microM) increased secretion, whereas neither PACAP1 - 27, PACAP1 - 38 nor secretin (up to 10 microM) increased mucus output. In contrast, VIP, PACAP1 - 27 and PACAP1 - 38 concentration-dependently inhibited cholinergic neural secretion, with an order of potency of VIP>PACAP 1 - 38>PACAP1 - 27. Neither PACAP1 - 27 nor PACAP1 - 38 altered the secretion induced by acetylcholine (ACh). 3 Secretin increased cholinergic neural secretion with a maximal increase of 190% at 1 microM. This potentiation was blocked by VIP or atropine. Similarly, secretin (1 microM) potentiated VIP (1 microM)-induced mucus output by 160%. Secretin did not alter exogenous ACh-induced secretion. VIP vs secretin competition curves suggested these two peptides were competing reversibly for the same receptor. 4 We conclude that, in ferret trachea in vitro, VIP and PACAPs inhibit cholinergic neural secretion via pre-junctional modulation of cholinergic neurotransmission. VIP and secretin compete for the same receptor, possibly a VIP1 receptor, at which secretin may be a receptor antagonist.     

Comparative effects of PACAP and VIP on pancreatic endocrine secretions and vascular resistance in rat.

1. The effects of pituitary adenylate cyclase-activating polypeptide (PACAP), vasoactive intestinal peptide (VIP) and secretin on pancreatic endocrine secretions and vascular resistance were investigated and compared in the isolated perfused pancreas of the rat. The PACAP/VIP receptor types involved have been characterized. 2. On insulin secretion, in the range 10(-11) to 10(-8) M, PACAP and VIP elicited a concentration-dependent biphasic response from pancreas perfused with 8.3 mM glucose; the peptides were equipotent. In contrast, secretin was ineffective in the range 10(-11) to 10(-9) M; at 10(-8) and 10(-7) M, it induced only low and transient insulin responses. On the other hand, the peptides did not modify the basal insulin release in the presence of a non stimulating glucose concentration (2.8 mM). 3. On glucagon secretion, PACAP and VIP (10(-11) to 10(-8) M) but also secretin (10(-9) to 10(-7) M) caused a concentration-dependent peak shaped response from pancreas perfused with 2.8 mM glucose; PACAP and VIP were equipotent and 20 times more potent then secretin. On the other hand, the peptides did not affect the glucagon release in the presence of 8.3 mM glucose. 4. On pancreatic vessels, in the range 10(-11) to 10(-9) M, the three peptides were equipotent in inducing a concentration-dependent sustained increase in pancreatic flow rate. On the other hand, at the high concentration of 10(-7) M PACAP but not VIP provoked a transient decrease of flow rate. 5. This study provides evidence for PACAP/VIP type II receptors mediating insulin and glucagon secretion as well as vasodilatation in rat pancreas. In addition, the different efficacies of secretin suggest that these effects are mediated by different PACAP/VIP type II receptor subtypes.     

Therapeutical approaches of vasoactive intestinal peptide as a pleiotropic immunomodulator

The vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are two neuropeptides belonging to the VIP/secretin/glucagon family of peptides. VIP/PACAP are present and released from both innervation and immune cells, particularly Th2 cells, and exert a wide spectrum of immunological functions controlling the homeostasis of immune system through different receptors expressed in various immunocompetent cells. VIP/PACAP have a general anti-inflammatory effect, both in innate and adaptive immunity. In innate immunity, VIP/PACAP inhibit the production of pro-inflammatory cytokines and chemokines from macrophages, microglia and dendritic cells. In addition, VIP/PACAP reduce the expression of costimulatory molecules (particularly CD80 and CD86) on the antigen-presenting cells, and therefore reduce stimulation of antigen-specific CD4(+) T cells. In terms of adaptive immunity, VIP/PACAP promote Th2-type responses, and reduce the pro-inflammatory Th1-type responses. Several of the molecular mechanisms involved in the inhibition of cytokine and chemokine expression, and in the preferential development and/or survival of Th2 effectors, are perfectly known. Therefore, VIP/PACAP and analogues have been recently proposed as very promising candidates, alternative to other existing treatments, for treating acute and chronic inflammatory and autoimmune diseases, such as septic shock, rheumatoid arthritis, multiple sclerosis, Parkinson's disease, Crohn disease, or autoimmune diabetes. The aim of this review is firstly to update our knowledge of the cellular and molecular events relevant to VIP function on the immune system; and secondly to gather together recent data that support its role as a type 2 cytokine. Recognition of the central functions VIP plays in cellular processes is focusing our attention on this "very important peptide" as an exciting new candidate for therapeutic intervention and drug development.     

Passage of VIP/PACAP/secretin family across the blood-brain barrier: therapeutic effects

In recent years, VIP/PACAP/secretin family has special interest. Family members are vasoactive intestinal peptide (VIP), pituitary adenylate cyclase-activating polypeptide (PACAP), secretin, glucagon, glucagon like peptide-1 (GLP(1)), GLP(2), gastric inhibitory peptide (GIP), growth hormone releasing hormone (GHRH or GRF), and peptide histidine methionine (PHM). Most of the family members present both in central nervous system (CNS) and in various peripheral tissues. The family members that are released into blood from periphery, especially gut, circulate the brain and they can cross the blood brain barrier. On the other hand, some of the members of this family that present in the brain, can cross from brain to blood and reach the peripheral targets. VIP, secretin, GLP(1), and PACAP 27 are transported into the brain by transmembrane diffusion, a non-saturable mechanism. However, uptake of PACAP 38 into the brain is saturable mechanism. While there is no report for the passage of GIP, GLP(2), and PHM, there is only one report that shows, glucagon and GHRH can cross the BBB. The passage of VIP/PACAP/secretin family members opens up new horizon for understanding of CNS effects of peripherally administrated peptides. There is much hope that those peptides may prove to be useful in the treatment of serious neurological diseases such as Alzheimer's disease, amyotropic lateral sclerosis, Parkinson's disease, AIDS related neuropathy, diabetic neuropathy, autism, stroke and nerve injury. Their benefits in various pathophysiologic conditions undoubtly motivate the development of a novel drug design for future therapeutics.     

Receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide in the goose cerebral cortex

Receptors for vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) in the goose cerebral cortex were characterized using two approaches: (1) in vitro radioreceptor binding of [(125)I]-VIP, and (2) effects of peptides from the VIP/PACAP/secretin family on cyclic AMP formation. The binding of [(125)I]-VIP to goose cortical membranes was rapid, stable, and reversible. Saturation analysis resulted in a linear Scatchard plot, suggesting binding to a single class of receptor binding sites with a high affinity (K(d)=0.76 +/- 0.13 nM) and high capacity (B(max)=70 +/- 7 fmol/mg of protein). Various peptides displaced the specific binding of 0.12 nM [(125)I]-VIP to the goose cerebral cortical membranes in a concentration-dependent manner. The relative rank order of potency of the tested peptides to inhibit [(125)I]-VIP binding to the goose cerebrum was: PACAP(38) asymptotically equal to mammalian VIP > or = PACAP(27) asymptotically equal to chicken VIP > PHI (peptide histidine-isoleucine) > secretin (inactive). About 52% of specific [(125)I]-VIP binding sites in the goose cerebral cortex was sensitive to 5'-guanylimidodiphosphate [Gpp(NH)p], a nonhydrolyzable analogue of GTP. PACAP(38) and PACAP(27) potently stimulated cyclic AMP formation in the goose cerebral cortical slices in a concentration-dependent manner, displaying EC(50) values of 45.5 nM and 51.5 nM, respectively. Chicken VIP was markedly less potent than both forms of PACAP, mammalian VIP only weakly affected the nucleotide production, while effects evoked by PHI were negligible. It is concluded that the cerebral cortex of goose contains VPAC type receptors that are labeled with [(125)I]-VIP and are positively linked to cyclic AMP formation. In addition, the observed stronger action of PACAP, when compared to VIP, on cyclic AMP production in this tissue suggests its interaction with both PAC(1) and VPAC receptors.     

Addition of the (28–38) peptide sequence of PACAP to the VIP sequence modifies peptide selectivity and efficacy

Chimeric peptides were synthesized by adding the C-terminal extension 28-38 of the pituitary adenylate cyclase activating polypeptide (PACAP) to the sequences (1–27), (2–27), (3–27) and (6–27) of VIP. The capacity of these peptides to occupy the selective PACAP- and the non-selective PACAP-VIP receptors and to stimulate adenylate cyclase activity was studied in Chinese hamster ovary (CHO) cells expressing the recombinant receptors. The results were compared to those obtained with VIP and the corresponding VIP fragments. The presence of the (28–38) PACAP extension increased at least 100-fold the VIP- or VIP fragment affinities for the selective PACAP receptor but not for the non-selective PACAP-VIP receptors. Furthermore, on both receptors, the extension increased peptide intrinsic activity: VIP(3–28) was a partial agonist; while VIP(3–27)/PACAP(28–38) was as potent as VIP and was apparently a full agonist; VIP(6–28) had no intrinsic activity, but VIP(6–27)/PACAP(28–38) was a partial agonist. These results suggest: (1) the presence of a specific domain for the (28–38) PACAP sequence on the selective PACAP receptor; and (2) a stabilizing effect of the (28–38) PACAP sequence on the structure of N-terminally truncated VIP. © Munksgaard 1996.     

Physiological significance of pituitary adenylate cyclase-activating polypeptide (PACAP) in the nervous system

Pituitary adenylate cyclase-activating polypeptide (PACAP) has been conserved remarkably during evolution and is widely expressed in the nervous system across phyla. PACAP has an amino acid sequence homology of 68% with that of vasoactive intestinal polypeptide (VIP) and of 37% with that of secretin, indicating that PACAP is a member of the VIP/glucagon/secretin superfamily. PACAP exerts its actions via three heptahelical G-protein-linked receptors: one PACAP-specific (PAC1) receptor and two receptors (VPAC1 and VPAC2) shared with VIP. PACAP stimulates several different signaling cascades in neurons, leading to the activation of adenylate cyclase, phospholipase C, and mitogen-activated protein kinase and mobilization of calcium. Although PACAP and VIP have no apparent homology with calcitonin and parathyroid hormone (PTH), PAC1, VPAC, secretin, glucagon, glucagon-like peptide 1, growth hormone-releasing hormone, calcitonin, and PTH/PTH-related peptide receptors are related to each other and constitute a subfamily of the G-protein-coupled receptors. Distribution analysis of PACAP and its receptors and pharmacological studies have elucidated its pleiotropic effects in the central and peripheral nervous systems. However, the relevance of the pharmacological PACAP effects to the actual physiological activities of endogenous PACAP has not been addressed, because potent and selective low-molecular-weight PACAP antagonists have not yet been developed. To assess the function of PACAP in vivo, we have recently generated PAC1 receptor- and PACAP-targeted mice, and provided evidence that PACAP plays a previously uncharacterized role in the regulation of psychomotor behaviors. In this review, we focus on the physiological and or pathophysiological roles mediated by PACAP in the nervous system.     

Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) activate protein kinase C in chick cerebral cortex

Pituitary adenylate cyclase-activating polypeptide (PACAP38) and vasoactive intestinal peptide (VIP) were tested for their ability to influence protein kinase C (PKC) activity in the chick cerebral cortical slices. Thirty minutes incubation of the chick tissue with PACAP38 (0.1-1 microM) or VIP (0.3-3 microM) produced significant and concentration-dependent changes in PKC activity. Both peptides enhanced the enzyme activity in cell membrane preparation, and decreased it in cytosol preparation obtained from cerebral cortical slices. These changes in PKC activity suggest that PACAP and VIP are capable of activating this enzyme in cerebral cortex of chick.     

Effects of PACAP, VIP and related peptides on cyclic AMP formation in rat neuronal and astrocyte cultures and cerebral cortical slices

The effects of pituitary adenylate cyclase-activating polypeptide (PACAP), vasoactive intestinal peptide (VIP), peptide histidine-isoleucine (PHI) and peptide histidine-methionine (PHM) on cyclic AMP formation were studied in parallel on rat cerebral cortical slices, primary neuronal cultures and primary glial (astrocyte) cultures. PACAPappeared to be the most potent agent in all biological systems. The rank order of the peptides' potency was as follows: PACAP > VIP > PHI = PHM for cortical slices and neuronal cell cultures, and PACAP > PHM approximately VIP > PHI for glial cell cultures. The cyclic AMP responses to the tested peptides, especially to PACAP, were distinctly larger in glial cell cultures than in neuronal cell cultures or brain slices. In an additional study, the cyclic AMP response to helodermin and secretin, as well as isoprenaline, histamine and forskolin, were tested in parallel on glial and neuronal cell cultures, and directly compared with the actions of PACAP. Helodermin and isoprenaline showed clearly stronger activity in glial cell cultures, yet their activity was much weaker than that of PACAP, whereas the effect of forskolin was only 2 times larger in glial cells than in neuronal cultures; histamine had no effect in any cell culture, while secretin produced a small but significant effect only in glial cells. The obtained results suggest that the astrocyte compartment of the rat brain may be the main target for such peptides as PACAP, VIP, or structurally related PHI/PHM or helodermin.     

Neuronal and smooth muscle receptors involved in the PACAP- and VIP-induced relaxations of the pig urinary bladder neck

BACKGROUND AND PURPOSE: As pituitary adenylate cyclase-activating polypeptide 38 (PACAP 38)- and vasoactive intestinal peptide (VIP) are widely distributed in the urinary tract, the current study investigated the receptors and mechanisms involved in relaxations induced by these peptides in the pig bladder neck. EXPERIMENTAL APPROACH: Urothelium-denuded strips were suspended in organ baths for isometric force recordings and the relaxations to VIP and PACAP analogues were investigated. KEY RESULTS: VIP, PACAP 38, PACAP 27 and [Ala(11,22,28)]-VIP produced similar relaxations. Inhibition of neuronal voltage-gated Ca(2+) channels reduced relaxations to PACAP 38 and increased those induced by VIP. Blockade of capsaicin-sensitive primary afferents (CSPA), nitric oxide (NO)-synthase or guanylate cyclase reduced the PACAP 38 relaxations but failed to modify the VIP responses. Inhibition of VIP/PACAP receptors and of voltage-gated K(+) channels reduced PACAP 38 and VIP relaxations, which were not modified by the K(+) channel blockers iberiotoxin, charybdotoxin, apamin or glibenclamide. The phosphodiesterase 4 inhibitor rolipram and the adenylate cyclase activator forskolin produced potent relaxations. Blockade of protein kinase A (PKA) reduced PACAP 38- and VIP-induced relaxations. CONCLUSIONS AND IMPLICATIONS: PACAP 38 and VIP relax the pig urinary bladder neck through muscle VPAC(2) receptors linked to the cAMP-PKA pathway and involve activation of voltage-gated K(+) channels. Facilitatory PAC(1) receptors located at CSPA and coupled to NO release, and inhibitory VPAC receptors at motor endings are also involved in the relaxations to PACAP 38 and VIP, respectively. VIP/PACAP receptor antagonists could be useful in the therapy of urinary incontinence produced by intrinsic sphincter deficiency.     

Pituitary adenylate cyclase-activating polypeptide, helospectin, and vasoactive intestinal polypeptide in human corpus cavernosum.

1. The distribution and effects of pituitary adenylate cyclase-activating polypeptide (PACAP-27 and -38), helospectin (Hel-1 and Hel-2), and vasoactive intestinal polypeptide (VIP), were investigated in isolated preparations of human corpus cavernosum (CC). 2. Immunohistochemistry revealed coinciding profiles of nerve structures that showed immunoreactivities for VIP and PACAP, and VIP and Hel. Confocal microscopy showed the co-existence of VIP- and PACAP-immunoreactivities, and VIP- and Hel-immunoreactivities in most (90%) varicose nerve structures. 3. As determined by radioimmunoassay, the amounts of VIP, PACAP-27, and PACAP-38 in the preparations were 61.7 +/- 11.6, 0.1 +/- 0.05, and 3.7 +/- 0.5 pmol g-1 wet weight of tissue (pmol g-1 wet wt.), respectively. In tissue from patients with diabetes, the content of VIP was lower (13.7 +/- 0.5 pmol g-1 wet wt.), whereas that of PACAP (-27 and -38) was unchanged. 4. Cyclic nucleotide levels were determined in preparations exposed to PACAP-27, PACAP-38, Hel-1, Hel-2, and VIP. All the peptides, but Hel-2, significantly increased the concentrations of cyclic AMP, whereas the levels of cyclic GMP were unchanged. 5. The peptides concentration-dependently relaxed noradrenaline-contracted preparations. The order of potency was VIP > PACAP 27 > Hel-1 > Hel-2 > PACAP-38. 6. Hel-1, VIP and PACAP-27 effectively counteracted electrically induced contractions. At 10(-6) M, the highest peptide concentration used, the inhibitory effects obtained reached 96 +/- 3%, 87 +/- 6%, and 80 +/- 3%, respectively. 7. The results suggest that PACAP and Hel-1 are co-localized with VIP in nerve structures within the human cavernous tissue, and that the peptides are effective relaxants of CC preparations in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pituitary adenylate cyclase activating polypeptide is a potent vasodilator and oedema potentiator in rabbit skin in vivo.

1. The effects of pituitary adenylate cyclase activating polypeptide (PACAP) on microvascular blood flow and plasma protein leakage were investigated in rabbit skin in vivo. 2. Intradermal injection of PACAP38, the 38 amino acid form of the peptide, caused a dose-dependent increase in blood flow measured by a 133Xe clearance technique. An equivalent increase in blood flow was induced by 10(-12) mol per site of PACAP38, 10(-12) mol per site of human alpha-calcitonin gene-related peptide (CGRP) and 10(-10) mol per site of vasoactive intestinal polypeptide (VIP). 3. The vasodilator activity of PACAP38 was not significantly different from that of the 27 amino acid form of the peptide, PACAP27, when measured with a laser Doppler flow meter, causing a 104 +/- 14% compared with 110 +/- 18% increase above basal blood flow at 10(-12) mol per site respectively. 4. At 10(-12) mol per site the effect of PACAP38 was longer lasting than that of CGRP. Blood flow remained significantly increased above control at 2 h with PACAP38 (P less than 0.05) whereas blood flow after intradermal CGRP had returned to control values by this time. 5. PACAP38 injected alone had no significant effect on microvascular leakage of 125I-labelled albumin. However, PACAP38 significantly potentiated bradykinin-induced oedema where it was approximately 100 fold more potent than VIP. 6. Oedema potentiation induced by PACAP38 was not inhibited by indomethacin at a dose which did inhibit potentiation of bradykinin-induced oedema by arachidonic acid.(ABSTRACT TRUNCATED AT 250 WORDS)     

Transgenic mice overexpressing PACAP in pancreatic beta-cells: acute and chronic effects on insulin and glucose homeostasis

PACAP belongs to the vasoactive intestinal polypeptide (VIP)/secretin/glucagon superfamily, which also includes glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). PACAP shares an insulinotropic property with the latter two peptides; for instance, it stimulates insulin secretion from islets in a glucose-dependent manner at femtomolar concentrations. However, the pathophysiological significance of PACAP in diabetes remains largely unknown, for several reasons, including a lack of low-molecular weight PACAP ligands and a lack of suitable animal models. As an approach to understanding PACAP's pancreatic function in vivo, we have recently generated transgenic mice overexpressing PACAP in islet beta cells under the control of human insulin promoter (Tg mice). As a consequence, it has been demonstrated that in addition to stimulating insulin secretion, PACAP has long-term effects on pancreatic endocrine cells, including proliferation of beta cells during streptozotocin-induced diabetes development as well as aging. These observations provide additional information to support the possibility that drugs associated with PACAP-signaling pathways might be of therapeutic value for the treatment of diabetes. In this review, we briefly summarize these previous studies using Tg mice and also focus on the physiological and pathophysiological roles mediated by PACAP during diabetes development.     

Pharmacological profiling of neuropeptides on rabbit vaginal wall and vaginal artery smooth muscle in vitro

Background and purpose:Hypothalamic neuropeptides centrally modulate sexual arousal. However, the role of neuropeptides in peripheral arousal has been ignored. Vascular and non-vascular smooth muscle relaxation in the vagina is important for female sexual arousal. To date, in vitro studies have focused on vaginal strips with no studies on vaginal arteries. The aim of this study was to compare the effects of sexual hypothalamic neuropeptides on rabbit vaginal wall strips and arteries.Experimental approach:Tissue bath and wire myography techniques were used to measure isometric tension from strips and arteries, respectively.Key results:Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) relaxed both preparations, effects that were only antagonized by the VIP/PACAP antagonist VIP6-28 (10 nM) and the PAC(1) antagonist PACAP 6-38 (1 muM). The melanocortin agonist alpha-melanocortin-stimulating hormone (1 muM), but not bremelanotide (1 muM), also relaxed both preparations. Oxytocin and vasopressin contracted vaginal preparations, which could be antagonized by the V(1A) antagonist SR 49059. Neuropeptide Y (NPY) and the NPY Y(1) agonist Leu(31), Pro(34) NPY only contracted arteries, which was antagonized by the NPY Y(1) receptor antagonist BIBP 3226. Melanin-concentrating hormone (MCH; 1 muM) contracted arteries.Conclusion and implications:Hypothalamic neuropeptides can exert contractile and relaxant effects on vaginal strips and arteries. NPY Y(1), V(1A), MCH(1) antagonists as well as VIP/PAC(1) agonists may have therapeutic potential in both central and peripheral female sexual arousal. Differences in effect of neuropeptides between preparations raise the question of which preparation is important for female sexual arousal.British Journal of Pharmacology (2008) 155, 236-243; doi:10.1038/bjp.2008.253; published online 30 June 2008.     

Pituitary adenylate cyclase activating peptide mediates inhibitory nonadrenergic noncholinergic relaxation

We investigated the contribution of pituitary adenylate cyclase activating peptide (PACAP) to inhibitory nonadrenergic noncholinergic (inhibitory-NANC) relaxation of tracheal smooth muscle in cats. We also investigated the roles of vasoactive intestinal peptide (VIP) and nitric oxide (NO) on this function. Smooth muscle strips prepared from feline trachea were precontracted with 1 microM serotonin, and inhibitory-NANC relaxation was induced by electrical-field stimulation in the presence of atropine and propranolol. PACAP-(6-38) (a selective antagonist of PACAP; 1, 3 and 10 microM), VIP-(10-28) (a selective antagonist of VIP; 1, 3 and 10 microM) and N(omega)-nitro-L-arginine methyl ester (L-NAME, a selective NO synthase inhibitor; 3, 10 and 30 microM) each partially but significantly attenuated the amplitude of inhibitory-NANC relaxation. The effects of PACAP-(6-38) and VIP-(10-28) were additive. Addition of PACAP-(6-38) and/or VIP-(10-28) further attenuated relaxation in the presence of L-NAME. These results suggest that PACAP, VIP and NO contribute to the relaxation induced by inhibitory-NANC in tracheal smooth muscle in cats, and that they mediate this relaxation via different pathways.     

Pharmacology and functions of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide: IUPHAR review 1

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are members of a superfamily of structurally related peptide hormones that includes glucagon, glucagon-like peptides, secretin, gastric inhibitory peptide (GIP) and growth hormone-releasing hormone (GHRH). VIP and PACAP exert their actions through three GPCRs – PAC₁, VPAC₁ and VPAC₂– belonging to class B (also referred to as class II, or secretin receptor-like GPCRs). This family comprises receptors for all peptides structurally related to VIP and PACAP, and also receptors for parathyroid hormone, corticotropin-releasing factor, calcitonin and related peptides. PAC₁ receptors are selective for PACAP, whereas VPAC₁ and VPAC₂ respond to both VIP and PACAP with high affinity. VIP and PACAP play diverse and important roles in the CNS, with functions in the control of circadian rhythms, learning and memory, anxiety and responses to stress and brain injury. Recent genetic studies also implicate the VPAC₂ receptor in susceptibility to schizophrenia and the PAC₁ receptor in post-traumatic stress disorder. In the periphery, VIP and PACAP play important roles in the control of immunity and inflammation, the control of pancreatic insulin secretion, the release of catecholamines from the adrenal medulla and as co-transmitters in autonomic and sensory neurons. This article, written by members of the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR) subcommittee on receptors for VIP and PACAP, confirms the existing nomenclature for these receptors and reviews our current understanding of their structure, pharmacology and functions and their likely physiological roles in health and disease. More detailed information has been incorporated into newly revised pages in the IUPHAR database (http://www.iuphar-db.org/DATABASE/FamilyMenuForward?familyId=67).

LINKED ARTICLES

This article is part of a themed section on Secretin Family (Class B) G Protein-Coupled Receptors. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.166.issue-1     

Pituitary adenylate cyclase-activating polypeptide: a novel, long-lasting, endothelium-independent vasorelaxant

The vasoactivity of the 27- and 38-amino acid forms of the novel peptide pituitary adenylate cyclase-activating polypeptide (PACAP) was tested in vitro. Both forms of PACAP caused endothelium-independent vasodilation (assayed by their vasodilator action on rabbit aorta). When superfused for 1 min the relaxation EC50 of PACAP27 was 23 +/- 8 nM and of PACAP38 was 152 +/- 66 nM. PACAP was 100-fold more potent than vasoactive intestinal polypeptide (VIP) (PACAP27 shows 68% amino acid sequence homology with VIP), and had a prolonged duration of action, a 1 min exposure to 1 microM PACAP27 lasting 135 +/- 7 min and to 1 microM PACAP38 108 +/- 3 min. Adenylate cyclase activity in homogenates of rabbit aortic smooth muscle cells was increased by PACAP27 and PACAP38 with EC50s of 4.4 and 0.73 nM, respectively. PACAP27 and PACAP38 are potent, long-lasting, endothelium-independent vasodilators.     

Immunomodulatory roles of VIP and PACAP in models of multiple sclerosis

Multiple sclerosis (MS) is a progressive neurodegenerative disease affecting myelin and axons, which is perpetuated by autoreactive lymphocytes and other inflammatory cell types. Because of the multifactorial nature of this disease, therapies targeting a single process may not be sufficient to halt its progression. VIP and PACAP are two neuropeptides shown to regulate multiple aspects of innate and adaptive immunity, and can also act independently on neural cells to promote their survival and regeneration. Animal studies have proven the efficacy of these peptides for the treatment of several models of neural inflammatory disorders, including those which, like MS, have major Th1/Th17 components. In this review, the immunomodulatory actions of VIP and PACAP will be discussed, with particular emphasis on their potential significance in MS.