General

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). At least three receptors for PACAP exist in mammals, two of which are also high-affinity receptors for VIP [40].

VIP

VIP, first isolated from porcine intestine as a 28-amino acid (aa) peptide capable of inducing vasodilatation in the canine femoral artery [106-107], has subsequently been shown to have many other actions as a neuroendocrine hormone, putative neurotransmitter and cytokine. The presence of VIP and specific VIP binding sites in defined pathways in the brain indicate that it may play an important role in central nervous system (CNS) function [10,70]. 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 [108]. VIP may also promote neuronal survival [11] and regulate glycogen metabolism in the cerebral cortex [113]. VIP stimulates prolactin secretion from the pituitary [98] and catecholamine release from the adrenal medulla [69]. In the immune system, VIP regulates T cell traffic and inhibits mitogen-activated proliferation of T cells by inhibiting interleukin-2 production [84]. Other actions of VIP include stimulation of electrolyte secretion and protection against oxidant injury [31,104-105].

In common with the precursors of a number of other neuroendocrine peptides, the VIP precursor polypeptide (prepro-VIP) contains sequences encoding several additional biologically active peptides, including either peptide histidine isoleucine (PHI: in non-human mammals) [121] or peptide histidine methionine (PHM: the human equivalent of PHI) [49] and peptide histidine valine (PHV), a C-terminally extended form of PHI and PHM [146].

PACAP

PACAP was first identified as a 38aa peptide (PACAP-38) from ovine hypothalamus that stimulated adenylate cyclase in rat anterior pituitary cells in culture [73]. Subsequently, a C-terminally truncated, 27aa form of the peptide (PACAP-27) was isolated from the same source [74]. In the CNS, PACAP and the mRNA encoding its precursor are most abundant in the hypothalamus, with lower levels in many other brain regions [23]. PACAP is also present in a number of peripheral tissues, including the gastrointestinal tract, adrenal gland and testis [4,23]. Although first isolated as a hypophysiotropic hormone, the role of PACAP in the regulation of pituitary hormone secretion is still poorly understood [96]. However, in the CNS, PACAP released from retinal afferents to the rat suprachiasmatic nucleus has been proposed to function as a daytime regulator of the biological clock [37]. PACAP is expressed in sympathetic neurons and in the cholinergic innervation of the adrenal medulla, where it is though to facilitate prolonged secretion of catecholamines under conditions of high stress [35,94]. PACAP is also thought to regulate exocrine and endocrine secretion from the pancreas [144]. For a recent review of the structure and functions of PACAP and its receptors, see [133].

Receptor types

Ligand binding studies [112] suggested the existence of at least two distinct receptors for PACAP, 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'). Based on the relative potencies of natural and synthetic VIP analogues, it was later suggested that two types of high affinity VIP (PACAP type II) receptors existed in rat and human tissues. In addition to the 'classical' VIP receptors from intestinal cells [60], a second receptor was identified in the human SUP-T1 lymphoblast cell line [102] and in lung cancer cell lines [66]. Subsequently, two high-affinity receptors for both VIP and PACAP ('PACAP type II receptors', now referred to as VPAC₁ and VPAC₂) and a third receptor selective for PACAP (the 'PACAP type I receptor', now referred to as PAC₁) were cloned. Progress in characterising the functions of the three receptor types has been hindered by the limited number of selective pharmacological tools available. Briefly, [Ala^11,22,28]VIP and [K¹⁵, R¹⁶, L¹⁷]VIP(3-7)/GRF(8-27) are selective agonists of the VPAC₁ receptor and PG 97-269 is a selective antagonist. Ro 25-1392 is a VPAC₂ agonist but there is no highly selective VPAC₂ antagonist yet. Maxadilan is an agonist of PAC₁ and Max.d.4 (maxadilan Δ24-42) and M65 (maxadilan Δ25-41) are 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 does not discriminate between PAC₁ and VPAC₂ receptors.

VPAC receptors

For recent critical reviews of the pharmacology and signalling properties of VPAC₁ and VPAC₂ receptors, see [61-63].

The VPAC₁ receptor, which responds to VIP and PACAP with comparable affinity ('PACAP type II' pharmacology) was first isolated from rat lung [48]. This receptor is widely distributed in the CNS, most abundantly in the cerebral cortex and hippocampus [48,126], in peripheral tissues including liver, lung and intestine [42,46,48,55,100-101,115,126] and in T lymphocytes [20]. There are important differences between species in the pharmacology of VPAC₁ receptors [16]. Selective VPAC₁ receptor agonists [28,80] and antagonists [27] have been described.

The VPAC₂ receptor, first cloned from rat olfactory bulb [67] also responds to VIP and PACAP with comparable affinity ('PACAP type II' pharmacology). 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 [110,126]. The receptor is also present in many peripheral tissues, including smooth muscles in the cardiovascular, gastrointestinal and reproductive systems [3,42,47,58,100-101,126,142]. A number of selective peptide agonists [29,82-83,125,143] and an antagonist with some selectivity for the VPAC₂ receptor [76] have been described.

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 [K¹⁵,R¹⁶,L¹⁷]VIP(3-7)/GRF(8-27) (KRL-VIP) and the VPAC₂ selective agonist Ro25-1553 to distinguish the two receptor types [42,100-101]. [¹²⁵I]-Ro25-1553 can also be used to localise VPAC₂ receptors [42,100-101,136].

PAC receptors

The PAC₁ receptor, first cloned from a rat pancreatic acinar carcinoma cell line [91] recognises PACAP-27 and PACAP-38 with much higher potency than VIP. Messenger RNA 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 [43,111]). The receptor is also expressed abundantly in the embryonic nervous system [109,141,148] and in a number of peripheral tissues, most abundantly in the adrenal medulla [75,100-101,112,114]. 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 [103,112]. The difference between the two receptor subtypes may reflect differences in G protein-coupling and second messenger mechanisms [128] or result from alternative splicing of PAC₁ receptor mRNA [88,114].

Unlike the VPAC₁ and VPAC₂ receptors, the PAC₁ receptor has numerous splice variants. Within the part of the PAC₁ receptor cDNA encoding the third intracellular loop, splice variants either containing or lacking each of two alternative exons ('hip' and 'hop') 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 [53,114]. 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 [92] 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 21aa deletion, has been reported in human and mouse [19,88]. Surprisingly, the human splice variant bound PACAP-27, PACAP-38 and VIP with similar high affinity and all three peptides stimulated cyclic AMP accumulation with similar potency [19]. Additional N-terminal splice variants resulting from splicing out of the 3rd, 4th and 5th exons of the human gene [19] and by insertion of an additional 72 base pairs encoding 24aa (exon 3a) between coding exons 3 and 4 [18] have also been described.

Receptor structure and activation

PAC₁, VPAC₁ and VPAC₂ receptors belong to the family B, also referred to as class II, of 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 [15,39]. For all family B receptors, the large N-terminal ectodomain plays a crucial role in ligand recognition, prompting structural studies of this domain [15,61,63]. As initially described for the mouse CRF₂ receptor [32], 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 [59,117] 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 [120]. The data are consistent with the two-site model for peptide binding to family B GPCRs 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 [15,61,63]. This latter contact region remains elusive since none structure for full-length family B GPCRs has been determined yet. However, the presence of a helix N-capping motif in cognate peptide ligands of all family 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 family B GPCR activation [79].

Functions

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 [13], PACAP [14,56], the VPAC₂ receptor [5,41], the VPAC₁ receptor [21] and the PAC₁ receptor [38,52,87,118] 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 suprachiasmatic nuclei (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 [14,38,56] show that PACAP plays a role in modulating the light-induced resetting of the behavioural rhythm and light-induced clock gene expression in the SCN. In contrast, VIP is synthesised 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 and behaviour [6,17,41,45]. VIP deficient mice also display a severely disrupted circadian phenotype, sharing many common features with that of VPAC₂ receptor null mice [6,13].

Both 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 [50,89] and overexpression of overexpression of PACAP in mouse pancreatic β-cells has been reported to enhance insulin secretion and ameliorate streptozotocin-induced diabetes [145] and to inhibit hyperinsulinemia and islet hyperplasia in agouti yellow mice [122]. 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 [5]. 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 [125].

There is persuasive evidence that VIP and PACAP play important roles in the control of immunity and inflammation (for review see [93]). 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 interleukin-6 [71]. 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 [24,138] and on transgenic mice overexpressing the VPAC₂ receptor in CD4 T cells [138-140] 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 [119]. VIP-deficient mice, on the other hand, exhibited a paradoxical resistance to EAE, with a failed entry of inflammatory cells into the CNS parenchyma [2], 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 [1], rheumatoid arthritis [54] and multiple sclerosis [26].

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 [72,86]. The PAC₁ receptor is also expressed in brain areas which have been 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 upregulated in the BNST following chronic stress, and heightened BNST PACAP signalling produces anxiogenic behavioural responses [36]. 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 [72,86]. Furthermore, the glucocorticoid response in PACAP null animals is altered after emotional stressors [116,124]. PAC₁ receptor signalling in the CNS also alters feeding behaviour [44,77]; PAC1 signalling decreases food intake and promotes anorexic-like responses, which may be related to enhanced anxiety. A polymorphism in the PAC₁ receptor has been associated with post-traumatic stress disorder (PTSD) in the female population [99].

There is also 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 [7-8,81]. In particular, high concentrations of PAC₁ receptors are found in the external granule cell layer of the cerebellum during the two postnatal weeks [9,148], a period of intense multiplication and migration of granule cells. Treatment of cultured granule cells with PACAP enhances cell survival and stimulates neurite outgrowth [12,25,57]. The neurotrophic effect of PACAP is mediated through two distinct mechanisms, i.e. activation of the adenylyl cyclase and phospholipase C pathways leads to inhibition of caspase-3 activity and promotion of cell survival [132], whereas activation of the adenylyl cyclase and MAP-kinase pathways regulates gene expression and causes differentiation of granule neurons [130-131,137]. Injection for 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 [131], suggesting that PACAP is a potent inhibitor of apoptosis in the cerebellum during the development. Recent studies have shown that PACAP reduces the volume of infarct in a model of focal cerebral ischemia [97]. In vitro PACAP also exerts a neuroprotective effect on cerebellar neurons against apoptotic cell death induced by ethanol [135], ceramides [129] and oxidative stress [134].

The presence of PACAP in primary sensory neurones and the PAC₁ receptor in the dorsal horn of the spinal cord [51] suggested a role for the PAC₁ receptor in pain responses. PAC₁ receptor knockout mice displayed impaired nociceptive responses to chemical, thermal and mechanical stimuli [52] and PACAP deficient mice also displayed abnormal pain responses [68].

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 [85].

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 [33-34,95], probably acting through VPAC₂ receptors. VPAC₂ receptors have also been implicated in the control of astrocyte proliferation [149]. NAP (davunetide), an active fragment of the VIP-inducted neuroprotective protein ADNP (activity-dependent neuroprotective protein) is in clinical development for the treatment of neurodegenerative disorders [30]. In studies of postnatal 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 [147]. Two recent publications from independent groups have found associations between copy number variation in the gene encoding the VPAC₂ receptor and susceptibility to schizophrenia [65,127]. 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 [90].

Other receptors

There is some evidence for the presence of PHI-selective receptors in mammalian tissues [64,78] and the cloning of a PHI-selective receptor from the goldfish Carassius auratus has been reported [123]. Although there is no evidence at present for the existence of a separate gene encoding a PHI receptor in mammals [22], it remains possible that mammalian receptors with novel pharmacology, encoded by novel genes, resulting from alternative splicing of known genes or by interaction of known genes with accessory proteins, may be discovered in the future.

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