Pharmacology and functions of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide: IUPHAR Review 1 (original) (raw)

Abstract

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

Keywords: accessory proteins, agonists and antagonists, class B GPCR, PAC1 receptor, PACAP, signal transduction, splice variant, VIP, VPAC1 receptor, VPAC2 receptor

Links to online information in IUPHAR-DB and the BPS Guide to Receptors and Channels

The endogenous peptide ligands – PACAP, VIP, PHI/PHM and PHV

Vasoactive intestinal peptide (VIP) was first isolated from porcine intestine as a 28-amino acid peptide, conserved in sequence between most mammals, capable of inducing vasodilatation in the canine femoral artery (Said and Mutt, 1970; 1972) and has subsequently been shown to have many other actions as a neuroendocrine hormone, putative neurotransmitter and cytokine. In common with the precursors of many other neuroendocrine peptides, the VIP precursor polypeptide (prepro-VIP) contains sequences encoding several additional biologically active peptides (Figure 1), including peptide histidine isoleucine [PHI; found in non-human mammals (Tatemoto and Mutt, 1981)], peptide histidine methionine [PHM; the human equivalent of PHI (Itoh et al., 1983)] and peptide histidine valine [PHV; a C-terminally extended form of PHI and PHM (Yiangou et al., 1987)]. The presence of VIP and specific VIP binding sites in defined pathways in the brain indicate that it may play an important role in CNS function (Besson et al., 1986; Martin et al., 1987). VIP is now widely accepted as a co-transmitter, with nitric oxide and carbon monoxide, of nonadrenergic, noncholinergic relaxation of both vascular and nonvascular smooth muscle (Said and Rattan, 2004) and with acetylcholine in exocrine glands (Fahrenkrug, 1993). VIP may also promote neuronal survival (Brenneman and Eiden, 1986) and regulate glycogen metabolism in the cerebral cortex (Sorg and Magistretti, 1992). VIP stimulates prolactin secretion from the pituitary (Reichlin, 1988) and catecholamine release from the adrenal medulla (Malhotra et al., 1988). In the immune system, VIP regulates T cell traffic and inhibits mitogen-activated proliferation of T cells by inhibiting IL-2 production (Ottaway, 1987). Other actions of VIP include stimulation of electrolyte secretion and protection against oxidant injury (Gozes and Brenneman, 1989; Said, 1991; 1996).

Figure 1.

Structures of the precursors of VIP and PACAP and the biologically active peptides that they encode. Structures of the human VIP and PACAP precursors are shown, with sites of proteolytic processing (basic amino acids and glycine residues that donate the C-terminal amide groups of the mature peptides) indicated in ovals. Amino acid sequences of the human peptides and sequence variations in rat and mouse are given in single letter nomenclature. PACAP-related peptide displays sequence homology to PHM but has not been shown to be biologically active.

Pituitary adenylate cyclase-activating polypeptide (PACAP) was first identified as a 38-amino acid peptide (PACAP-38) from ovine hypothalamus on the basis of its ability to stimulate cyclic AMP production in rat anterior pituitary cells in culture (Miyata et al., 1989). Subsequently, a C-terminally truncated, 27-amino acid form of the peptide (PACAP-27) was isolated from the same source (Miyata et al., 1990). The sequences of human, mouse, rat and sheep PACAP-38 are identical (Figure 1). In the CNS, PACAP and the mRNA encoding its precursor are most abundant in the hypothalamus, with lower levels in other brain regions (Ghatei et al., 1993). PACAP is also present in peripheral tissues, such as the gastrointestinal tract, adrenal gland and testis (Ghatei et al., 1993; Arimura and Shioda, 1995). PACAP is expressed in sympathetic neurons and in the cholinergic innervation of the adrenal medulla, where it is thought to facilitate secretion of catecholamines under conditions of high stress (Przywara et al., 1996; Hamelink et al., 2002). PACAP is also thought to regulate exocrine and endocrine secretion from the pancreas (Raufman et al., 1991; Yada et al., 1994). For a recent review of the structure and functions of PACAP and its receptors, see Vaudry et al. (2009).

The receptors: VPAC1, VPAC2 and PAC1

Radioligand binding studies using [125I]PACAP-27 (Shivers et al., 1991) suggested the existence of two distinct receptors for PACAP in rat tissues, one with much greater affinity for PACAP than for VIP (the ‘PACAP type I receptor’) and a second with high affinity for both PACAP and VIP (the ‘PACAP type II receptor’). Subsequently, two types of high-affinity VIP (PACAP type II) receptors were identified based on the relative potencies of natural and synthetic VIP analogues. In addition to the ‘classical’ VIP receptors from intestinal cells (Laburthe et al., 1983), receptors with different pharmacology were identified in the human SUP-T1 lymphoblast cell line (Robberecht et al., 1988) and in lung cancer cell lines (Luis and Said, 1990). Subsequently, two high-affinity receptors for both VIP and PACAP (‘PACAP type II receptors’) were cloned: the VPAC1 receptor, first isolated from rat lung (Ishihara et al., 1992) and the VPAC2 receptor, first cloned from rat olfactory bulb (Lutz et al., 1993). VPAC1 and VPAC2 receptors display comparable affinity for PACAP and VIP, whereas PACAP-27 and PACAP-38 are >100-fold more potent than VIP as agonists of most isoforms of the PAC1 receptor.

The VPAC1 receptor is widely distributed in the CNS, most abundantly in the cerebral cortex and hippocampus (Ishihara et al., 1992; Usdin et al., 1994), in peripheral tissues including liver, lung and intestine (Ishihara et al., 1992; Usdin et al., 1994; Ichikawa et al., 1995; Sreedharan et al., 1995; Kaltreider et al., 1997; Reubi, 2000; Reubi et al., 2000; Harmar et al., 2004) and in T lymphocytes (Delgado et al., 1996). In the CNS, the highest concentrations of messenger RNA encoding the VPAC2 receptor are found in the thalamus and suprachiasmatic nucleus (SCN) and lower levels in the hippocampus, brainstem, spinal cord and dorsal root ganglia (Usdin et al., 1994; Sheward et al., 1995). The receptor is also present in many peripheral tissues, including smooth muscles in the cardiovascular, gastrointestinal and reproductive systems (Inagaki et al., 1994; Usdin et al., 1994; Adamou et al., 1995; Krempels et al., 1995; Wei and Mojsov, 1996; Reubi, 2000; Reubi et al., 2000; Harmar et al., 2004).

The ‘PACAP type I receptor’, which recognizes PACAP-27 and PACAP-38 with much higher potency than VIP (now referred to as PAC1) was first identified in a rat pancreatic acinar carcinoma cell line (Pisegna and Wank, 1993). mRNA encoding this receptor is expressed predominantly in the CNS, most abundantly in the olfactory bulb, thalamus, hypothalamus, the dentate gyrus of the hippocampus and in granule cells of the cerebellum (Hashimoto et al., 1996; Shioda et al., 1997). The receptor is also highly expressed in the embryonic nervous system (Sheward et al., 1998; Waschek et al., 1998; Zhou et al., 1999) and in a number of peripheral tissues, most abundantly in the adrenal medulla (Shivers et al., 1991; Spengler et al., 1993; Moller and Sundler, 1996; Reubi, 2000; Reubi et al., 2000). There is apparent heterogeneity of PAC1 receptors in tissues and cell lines, where two types of ‘PACAP type I’ pharmacology have been observed: type IA receptors, with high affinity for both PACAP-27 and PACAP-38; and type IB receptors, with high affinity for PACAP-38 but low affinity for PACAP-27 (Robberecht et al., 1991; Shivers et al., 1991). The difference between the two receptor subtypes may reflect differences in G protein coupling and second messenger mechanisms (Van Rampelbergh et al., 1996) or result from alternative splicing of PAC1 receptor mRNA.

Splice variants and accessory proteins

The diversity and functional consequences of alternative splicing events in class B GPCRs have been reviewed recently (Furness et al., 2012). Splice variants differing in amino acid sequence in the extracellular N-terminal domain or the extracellular loops may display altered ligand affinity and selectivity, whereas splice variation in the intracellular loops or the C-terminus can influence signal transduction pathways. Although there is some evidence for the existence of splice variants of the VPAC1 and VPAC2 receptors, their functional importance is not yet clear (Dickson and Finlayson, 2009). In contrast, splice variation in the PAC1 receptor is well established, complex and functionally important. Within the part of the PAC1 receptor cDNA encoding the third intracellular loop, splice variants either containing or lacking each of two alternative exons (called ‘hip’ and ‘hop’ in rodents) exist. The hop exon exists in two forms (hop1 and hop2) as the result of the existence of two alternative splice acceptor sites three nucleotides apart. Thus, six possible splice variants, which differ in their intracellular signal transduction pathways, can be generated (Spengler et al., 1993; Journot et al., 1995). Four variants of the human PAC1 receptor (null, SV-1, SV-2 and SV-3) resulting from alternative splicing of sequences equivalent to hip and hop1 have also been described (Pisegna and Wank, 1996) and were shown to differ in their ability to activate phospholipase C (PLC). In addition, splice variation in the N-terminal extracellular domain of the PAC1 receptor has been reported. Splicing out of the 4th and 5th coding exons, leading to a 21 amino acid deletion, has been reported in human and mouse (Pantaloni et al., 1996; Dautzenberg et al., 1999). Surprisingly, the human splice variant, named ‘PAC1short’ bound PACAP-27, PACAP-38 and VIP with similar high affinity and all three peptides stimulated cyclic AMP accumulation with similar potency (Dautzenberg et al., 1999). Additional N-terminal splice variants resulting from splicing out of the 3rd, 4th and 5th exons of the human gene (Dautzenberg et al., 1999) and by insertion of an additional 72 base pairs (exon 3a) encoding a sequence of 24 amino acids between coding exons 3 and 4 (Daniel et al., 2001) have also been described.

Two class B receptors – the calcitonin receptor and the calcitonin receptor-like receptor – can form heteromers with members of a family of accessory proteins called RAMPs (receptor activity-modifying proteins 1, 2 and 3) to generate multiple distinct receptor types with different specificities for endogenous peptide ligands (Barwell et al., 2012). The VPAC1 receptor (but not VPAC2 or PAC1) has been shown to be able to interact with RAMPs; in this case ligand specificity is not altered but the VPAC1 receptor-RAMP2 heteromer displays altered signal transduction specificity, with significant enhancement of agonist-mediated phosphoinositide hydrolysis with no change in cyclic AMP stimulation (Christopoulos et al., 2003).

Although there is some evidence for the presence of PHI-selective receptors in mammalian tissues and the cloning of a PHI-selective receptor from the goldfish Carassius auratus has been reported (Tse et al., 2002), there is no convincing evidence at present for a separate PHI receptor in mammals. However, it remains possible that such a receptor, either encoded by a novel gene, or resulting from alternative splicing of known genes, by interaction of known genes with accessory proteins, or through homo/hetero-oligomerization, may be discovered in the future.

Pharmacology

For recent critical reviews of the pharmacology and signalling properties of VIP and PACAP receptors, see Laburthe et al., 2007; Dickson and Finlayson, 2009. Progress in characterizing the functions of the three receptor types has been hindered by the limited number of selective drugs available (Table 1). [Ala11,22,28]VIP (Nicole et al., 2000) and [Lys15,Arg16,Leu27]VIP(1–7)/GRF(8–27)-NH2 (frequently abbreviated as [K15,R16,L27]VIP(1–7)/GRF(8–27) in the literature; Gourlet et al., 1997b) are selective agonists of the VPAC1 receptor and PG 97–269 is a selective antagonist (Gourlet et al., 1997a). Ro 25–1392 (Xia et al., 1997) is the most selective VPAC2 agonist to date. There is no highly selective VPAC2 antagonist as yet: PG99-465 (Moreno et al., 2000) has been used as a selective VPAC2 receptor antagonist in a number of physiological studies, but has been reported to be a partial agonist of VPAC2 in some functional assays (EC50= 5 nM) and act as a full agonist at VPAC1 (EC50= 8 nM) and PAC1 (EC50= 71 nM) receptors (Dickson et al., 2006). The tissue distribution of VPAC1 and VPAC2 receptors can be determined by in vitro receptor autoradiography using [125I]-VIP as the radioligand and displacement with the VPAC1 selective agonist [Lys15,Arg16,Leu27]VIP(1–7)/GRF(8–27)-NH2 and the VPAC2 selective agonist Ro 25-1553 to distinguish the two receptor types (Reubi et al., 2000; Harmar et al., 2004). [125I]-Ro 25-1553 can also be used to localize VPAC2 receptors (Vertongen et al., 1997; Reubi et al., 2000; Harmar et al., 2004).

Table 1.

Useful pharmacological tools for the characterization of VIP and PACAP receptors

The most selective agonist of PAC1 receptors is maxadilan, a peptide isolated from the salivary glands of sand flies (Lutzomyia longipalpis), which has no sequence homology to VIP or PACAP (Moro and Lerner, 1997). Max.d.4 (maxadilan Δ24–42) and M65 (maxadilan Δ25–41; Uchida et al., 1998) are synthetic variants of maxadilan, which display activity as PAC1 antagonists but the use of these peptides has been limited due to problems with their availability. Finally, it is important to note that although PACAP(6–38) has been used as a PAC1 receptor antagonist in many studies, it also exhibits high potency at VPAC2 receptors (Dickinson et al., 1997).

Receptor structure and signal transduction mechanisms

For all class B receptors, the large N-terminal ectodomain plays a crucial role in ligand recognition, prompting structural studies of this domain (Laburthe and Couvineau, 2002; Laburthe et al., 2007; Couvineau and Laburthe, 2012a, b). As initially described for the mouse CRF2 receptor (Grace et al., 2004), the structure comprises a crucial sushi domain characterized by two antiparallel β sheets and stabilized by three disulphide bonds and a salt bridge sandwiched between aromatic rings of two tryptophan residues. Structures of the ectodomains of PAC1 receptor (Sun et al., 2007; Kumar et al., 2011) and VPAC2 receptors (PDB ID: 2X57) have been determined by X-ray or NMR and a structural model of the VPAC1 receptor obtained by homology modelling associated with photoaffinity experiments (Tan et al., 2006). Photoaffinity labelling has also demonstrated that the ectodomain of the PAC1 receptor is the major binding site for PACAP (Dejda et al., 2011). The data are consistent with the two-site model for peptide binding to class B GPCRs (Figure 2), in which the C-terminal and central α-helical parts of the peptide hormone interact with the sushi domain in the N-terminal ectodomain (N-ted) ultimately positioning the N-terminus of the peptide to contact the transmembrane region resulting in receptor activation (Laburthe and Couvineau, 2002; Laburthe et al., 2007; Bourgault et al., 2009; Couvineau and Laburthe, 2012b). This latter contact region remains elusive since no structure for a full-length class B GPCR has been determined yet. However, the presence of a helix N-capping motif in cognate peptide ligands of all class B receptors, including VIP and PACAP, supports that the folded backbone conformation of a N-cap is formed upon receptor binding and constitutes a key element underlying class B GPCR activation (Neumann et al., 2008).

Figure 2.

Schematic model of VPAC1 receptor activation. The receptor N-ted traps the central and C-terminal parts (6–28) of VIP (shown in blue) and positions the N-terminal part (1–5) of VIP (yellow circle) in the receptor core for activation (adapted from Laburthe et al., 2007).

Functions of VIP and PACAP receptors in the CNS

The widespread distribution of VIP and PACAP and their receptors in the brain and periphery has led to many hypotheses concerning the physiological functions of these receptors. However, the availability of mutant mice lacking VIP (Colwell et al., 2003), PACAP (Kawaguchi et al., 2003; Colwell et al., 2004), the VPAC2 receptor (Asnicar et al., 2002; Harmar et al., 2002), the VPAC1 receptor (Fabricius et al., 2011) and the PAC1 receptor (Hannibal et al., 2001; Jongsma et al., 2001; Otto et al., 2001b) has permitted experimental validation of a number of physiological functions for these receptors.

Both VIP and PACAP play roles in the control of circadian rhythms in the brain's ‘master clock’ in the SCN of the hypothalamus. Light entrains the SCN clock through a population of retinal ganglion cells that project to the SCN via the retinohypothalamic tract and contain both glutamate and PACAP. Studies of knockout mice lacking the PAC1 receptor or its ligand PACAP (Hannibal et al., 2001; 2008; Kawaguchi et al., 2003; Colwell et al., 2004) show that PACAP plays a role in modulating the light-induced resetting of the behavioural rhythm and light-induced clock gene expression and physiology in the SCN. In contrast, VIP is synthesized in a population of SCN neurones, many of which are thought to receive a direct retinal innervation, and acts on VPAC2 receptors, which are expressed throughout the SCN. Studies of knockout mice lacking the VPAC2 receptor indicate that this receptor is necessary for the generation of normal circadian rhythms of electrical activity, clock gene expression, physiology and behaviour (Harmar et al., 2002; Cutler et al., 2003; Hughes et al., 2004; Aton et al., 2005; Bechtold et al., 2008; Hannibal et al., 2011). VIP-deficient mice also display a severely disrupted circadian phenotype, sharing many common features with that of VPAC2 receptor null mice (Colwell et al., 2003; Aton et al., 2005).

Studies on PAC1 receptor knockout mice point to a role for presynaptic PAC1-mediated signalling at the mossy fibre synapse in long-term potentiation (LTP) and hippocampus-dependent associative learning (Otto et al., 2001a; Matsuyama et al., 2003). The PAC1 receptor is also expressed in brain areas implicated in the emotional control of behaviour, such as the amygdala, bed nucleus of the stria terminalis (BNST), hypothalamus, locus coeruleus and periaqueductal grey. Consistent with this, PACAP and PAC1 receptors are up-regulated in the BNST following chronic stress, and heightened BNST PACAP signalling produces anxiogenic behavioural responses (Hammack et al., 2010). PACAP and PAC1 receptor null mice demonstrate reduced anxiety behaviour and mice with a ubiquitous but not with a forebrain-specific deletion of the PAC1 receptor exhibited elevated locomotor activity with strongly reduced anxiety-like behaviour (Otto et al., 2001a; Matsuyama et al., 2003). Furthermore, the glucocorticoid response in PACAP null animals is altered after emotional stressors (Stroth and Eiden, 2010; Tsukiyama et al., 2011). PAC1 receptor signalling in the CNS also alters feeding behaviour (Hawke et al., 2009; Mounien et al., 2009); PAC1 signalling decreases food intake and promotes anorexic-like responses, which may be related to enhanced anxiety. An intronic single nucleotide polymorphism in a putative oestrogen response element within the PAC1 receptor gene (ADCYAP1R1) has been associated with post-traumatic stress disorder in the female population (Ressler et al., 2011), consistent with evidence that stress and oestrogen regulate the expression of the gene in animal models.

There is clear evidence that PACAP exerts neurotrophic activities during development and may prevent brain damage provoked by various types of injury. PACAP and its receptors are expressed actively in the CNS during development (Basille et al., 1993; 1994). In particular, high concentrations of PAC1 receptors are found in the external granule cell layer of the rodent cerebellum during the first two postnatal weeks (Zhou et al., 1999; Basille et al., 2000), a period of intense multiplication and migration of granule cells. Treatment of cultured granule cells with PACAP enhances cell survival and stimulates neurite outgrowth (Cavallaro et al., 1996; Gonzalez et al., 1997; Kienlen Campard et al., 1997). The neurotrophic effect of PACAP is mediated through two distinct mechanisms, that is, activation of the adenylyl cyclase and PLC pathways leads to inhibition of caspase-3 activity and promotion of cell survival (Vaudry et al., 2000), whereas activation of the adenylyl cyclase and MAPK pathways regulates gene expression and causes differentiation of granule neurons (Villalba et al., 1997; Vaudry et al., 1998; 1999). Injection of PACAP at the surface of the cerebellum of rat pups augments the number of migrating granule cells and increases the thickness of the internal granule cell layer (Vaudry et al., 1999), suggesting that PACAP is a potent inhibitor of apoptosis in the cerebellum during the development. In adult animals, PACAP reduces the severity of injury in models of focal cerebral (Ohtaki et al., 2006) and retinal (Szabadfi et al., 2012) ischaemia. In vitro PACAP also exerts a neuroprotective effect on cerebellar neurons against apoptotic cell death induced by ethanol (Vaudry et al., 2002b), cisplatin (Aubert et al., 2008), ceramides (Vaudry et al., 2003) and oxidative stress (Vaudry et al., 2002a).

VIP is also thought to play a role in neurodevelopment and in neuroprotection following injury to the CNS. For example, VIP has been shown to be protective against excitotoxin-induced white matter lesions in neonatal mice (Gressens et al., 1997; 1999; Rangon et al., 2005), probably acting through VPAC2 receptors. VPAC2 receptors have also been implicated in the control of astrocyte proliferation (Zupan et al., 1998). VPAC2 receptors have also been implicated in the VIP-induced expression of the neuroprotective protein activity-dependent neuroprotective protein (ADNP) in astrocytes (Zusev and Gozes, 2004) and NAP (davunetide), an active fragment of ADNP, is in clinical development for the treatment of neurodegenerative disorders (Gozes, 2011). In studies of post-natal hippocampus in vitro, VPAC2 receptor activation was found to expand the pool of neural stem/progenitor cells by preventing either a neuronal or glial fate choice and by supporting their survival, whereas selective VPAC1 receptor activation promoted a neurogenic granule cell fate (Zaben et al., 2009). Two recent publications from independent groups have found associations between copy number variation in the gene encoding the VPAC2 receptor and susceptibility to schizophrenia (Levinson et al., 2011; Vacic et al., 2011). These findings have generated some excitement in the field because they may imply that the VPAC2 receptor is a potential target for the development of new antipsychotic drugs (Piggins, 2011).

Functions of VIP and PACAP receptors in the immune system

VIP and PACAP play important roles in the control of immunity and inflammation. PAC1 receptor mRNA is constitutively expressed in macrophages and monocytes. PACAP, acting through the PAC1 receptor appears to be protective against endotoxin-induced septic shock, acting at least in part by attenuating lipopolysaccharide-induced production of proinflammatory IL-6 (Martinez et al., 2002). VIP has potent effects in the immune system, influencing T cell differentiation and migration and modulating the production of cytokines by the two subsets of mouse helper T cells: T helper 1 (Th1) cells, which mediate classical delayed-type cellular immunity and T helper 2 (Th2) cells, which mediate hypersensitivity reactions, such as allergy. VPAC1 receptors are highly expressed constitutively on T cells, especially Th cells, whereas VPAC2 receptors are expressed marginally or not at all by unstimulated Th cells but are up-regulated to high levels by Th cell stimulation. Studies on VPAC2 receptor knockout mice (Goetzl et al., 2001; Voice et al., 2002) and on transgenic mice overexpressing the VPAC2 receptor in CD4 T cells (Voice et al., 2001; 2002; 2003) suggest that the receptor regulates the balance between Th1 and Th2 by stimulating production of more Th2-type cytokines, due to expansion of the Th2-type subset. PACAP knockout mice exhibited the predicted hyperinflammatory response in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis, with an enhanced Th1/Th2 cytokine profile, but also with a reduced expansion of regulatory T cells (Tan et al., 2009). VIP-deficient mice, on the other hand, exhibited a paradoxical resistance to EAE, with a failed entry of inflammatory cells into the CNS parenchyma (Abad et al., 2010), pointing to a critical role for VIP in T cell trafficking. VIP receptor agonists and antagonists may have therapeutic potential in the treatment of inflammatory and autoimmune diseases such as Crohn's disease (Abad et al., 2003), rheumatoid arthritis (Juarranz et al., 2004) and multiple sclerosis (Gonzalez-Rey et al., 2006).

Functions in the gastrointestinal tract

PACAP and VIP and their receptors are expressed widely in the gastrointestinal tract. In the gastric mucosa, PACAP-containing enteric nerve fibres have been described, which are co-localized with PAC1 receptors (Miampamba et al., 2002). PACAP appears to have diverse functions in the stomach that depend on whether the cell target expresses either PAC1 or VPAC1 receptors. PAC1 is expressed on gastric enterochromaffin-like (ECL) cells and involved in the regulation of gastric acid secretion, whereas VPAC1 is expressed by the somatostatin containing gastric D cells and thought to inhibit gastric acid secretion. In the rat stomach, PACAP released by enteric neurons innervating the mucosa appears to mediate the nocturnal increase in gastric acid secretion (Zeng et al., 1999). VIP knockout mice exhibit a reduction in gastrointestinal motility similar to that observed in patients with Hirschsprung's disease (Lelievre et al., 2007). These observations suggest that PACAP, VIP and their receptors appear to play an important role in the regulation of gastrointestinal function and underscore the importance of further studies in this area.

Relevance to cancer

The best-known association of VIP with cancer is the ‘watery diarrhoea syndrome’ (also known as ‘pancreatic cholera’ or Verner Morrison syndrome) caused by the ectopic secretion of VIP by some tumours (VIPomas), usually of non-β pancreatic islet cell origin (Modlin et al., 1978). The symptoms of this condition are thought to result from the action of VIP on VPAC1 receptors in the intestinal mucosa to stimulate chloride secretion and water movement into the intestinal lumen, an effect mimicked by selective VPAC1 receptor agonists in animal models (Tsutsumi et al., 2002).

Most of the commonly occurring human tumours express VPAC1 receptors (Reubi et al., 2000). VPAC2 expressing tumours are much rarer: they include a high proportion of gastrointestinal stromal tumours (Reubi et al., 2004) and also leiomyomata (benign smooth muscle neoplasms, e.g. uterine fibroids). Consistent with the role of PACAP in the CNS and the sympathoadrenal system, PAC1 receptors are often expressed in tumours of neuroectodermal origin (e.g. neuroblastoma, glioma, phaeochromocytoma and pituitary adenoma; Robberecht et al., 1993; 1994; Vertongen et al., 1996) as well as in endometrial carcinoma (Reubi et al., 2000). The use of radioactive ligands of VIP and PACAP receptors for imaging or therapy of tumours has met with limited success, perhaps due to difficulties in achieving selectivity for tumour tissue over normal tissues and in identifying analogues with appropriate pharmacokinetic properties. Numerous cell lines derived from tumours have been found to express receptors for VIP and PACAP (see http://www.tumor-gene.org/GPCR/gpcr.html) and have provided useful tools for the study of receptor function. For example, the first report of a receptor with VPAC2 pharmacology used SUP-T1 lymphoblasts (Robberecht et al., 1988) and PC12 phaeochromocytoma cells have been used extensively to study the effects of PACAP on cell survival, cell proliferation, neurite outgrowth and the underlying signalling pathways (Vaudry et al., 2009).

Other functions in the periphery

VIP and PACAP, acting through PAC1 and VPAC2 receptors on pancreatic β-cells, have been implicated in the control of pancreatic insulin secretion. PAC1 receptor-deficient mice display impaired insulinotropic response to glucose, reduced glucose tolerance and impaired glucagon response to insulin-induced hypoglycaemia (Jamen et al., 2000; Persson and Ahren, 2002) and overexpression of PACAP in mouse pancreatic β-cells has been reported to enhance insulin secretion and ameliorate streptozotocin-induced diabetes (Yamamoto et al., 2003) and to inhibit hyperinsulinemia and islet hyperplasia in agouti yellow mice (Tomimoto et al., 2004). VPAC2 receptor null mice have been reported to be able to maintain a normal response to glucose challenge with lower levels of insulin than wild-type mice, suggesting a significant increase in insulin sensitivity in the knockout mice (Asnicar et al., 2002). A selective peptide agonist of the VPAC2 receptor stimulated glucose-dependent insulin secretion in isolated rat and human pancreatic islets, increased insulin synthesis in purified rat islets and caused a dose-dependent increase in plasma insulin levels in fasted rats, suggesting that VPAC2 receptor agonists may be a useful therapy for the treatment of type 2 diabetes (Tsutsumi et al., 2002).

Consistent with the expression of PAC1 and VPAC1 receptors in adrenomedullar cells (Usdin et al., 1994; Moller and Sundler, 1996; Yon et al., 1998; Shioda et al., 2000), PACAP and VIP are potent activators of catecholamine release in vitro (Cheung and Holzwarth, 1986; Watanabe et al., 1992) and in vivo (Lamouche et al., 1999). Interestingly, PACAP strongly increases VIP mRNA expression in bovine chromaffin cells (Lee et al., 1999). Intravenous administration of PACAP enhances the secretion of corticosteroids in dog (Kawai et al., 1994) and calf (Edwards and Jones, 1994). In human, PACAP-induced stimulation of cortisol secretion from adrenal slices is suppressed by the β-adrenoceptor antagonists (Neri et al., 1996; Breault et al., 2000) suggesting that the effect of PACAP on corticosteroid secretion is mediated through its stimulatory action on catecholamine release.

The presence of PACAP in primary sensory neurones and the PAC1 receptor in the dorsal horn of the spinal cord (Jongsma et al., 2000) suggest a role for the PAC1 receptor in pain responses. PAC1 receptor knockout mice displayed impaired nociceptive responses to chemical, thermal and mechanical stimuli (Jongsma et al., 2001) and PACAP-deficient mice also displayed abnormal pain responses (Mabuchi et al., 2004).

Although most studies of PAC1 receptor knockout mice have found these animals to be superficially normal and viable, it has been reported that when crossed onto a C57BL/6 background, almost all PAC1 receptor knockout mice developed pulmonary hypertension and right heart failure after birth, suggesting an important role for PAC1-mediated signalling for the maintenance of normal pulmonary vascular tone during early postnatal life (Otto et al., 2004).

Perspectives

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. The development of drugs acting on these receptors may lead to new treatments for sleep disorders, stroke, neurodegenerative disorders and age-related memory impairment. Genetic studies also implicate the VPAC2 receptor as a potential target for the development of new antipsychotic drugs and suggest involvement of the PAC1 receptor in post-traumatic stress disorder. The role of VIP and PACAP in the gastrointestinal tract suggest that these hormones and their receptors would provide a therapeutic target for the management of gastric acid secretory disorders and disorders affecting gastrointestinal motility such as functional bowel syndromes. The involvement of VIP and PACAP in immune function suggests potential applications in the treatment of diseases such as Crohn's disease, rheumatoid arthritis and multiple sclerosis. Other peripheral functions of VIP and PACAP indicate potential importance in diabetes, pain and hypertension. The major impediment to translational research on VIP and PACAP is that all of the currently useful pharmacological tools are peptides. The first small molecule antagonists of PAC1 receptors (Beebe et al., 2008) and human VPAC2 receptors (Chu et al., 2010) have been described recently and may herald important breakthroughs in understanding the therapeutic opportunities offered by these receptors.

Acknowledgments

AJH is supported by IUPHAR, the British Pharmacological Society and the British Heart Foundation Centre of Research Excellence Award (RE/08/001).

Glossary

BNST

bed nucleus of the stria terminalis

EAE

experimental autoimmune encephalomyelitis

ECL

enterochromaffin-like

GHRH

growth hormone-releasing hormone

GIP

gastric inhibitory peptide

LTP

long-term potentiation

NC-IUPHAR

International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification

N-ted

N-terminal ectodomain

PACAP

pituitary adenylate cyclase-activating polypeptide

PHI

peptide histidine isoleucine

PHM

peptide histidine methionine

PHV

peptide histidine valine

RAMP

receptor activity-modifying protein

SCN

suprachiasmatic nuclei

Th1

T helper 1

Th2

T helper 2

VIP

vasoactive intestinal peptide

Conflicts of interest

Prof. Illana Gozes serves as a Director, Chief Scientific Officer at Allon Therapeutics Inc. clinically developing davunetide (NAP).

References

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