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. Author manuscript; available in PMC: 2022 Apr 1.
Published in final edited form as: Curr Opin Endocrinol Diabetes Obes. 2021 Apr 1;28(2):198–205. doi: 10.1097/MED.0000000000000617

PACAP/ VIP[Part 1]: Biology, Pharmacology, and new insights into their cellular basis of action/signaling which are providing new therapeutic targets

Terry W Moody a, Robert T Jensen b
PMCID: PMC7957349  NIHMSID: NIHMS1678034  PMID: 33449573

Abstract

Purpose of review

To discuss recent advances of VIP/PACAP receptors in pharmacology, cell biology and intracellular signaling in cancer.

Recent findings

Recent studies provide new insights into the pharmacology, cell biology of the VIP/PACAP system and show they play important roles in a number of human cancers, as well as in tumor growth/differentiation and are providing an increased understanding of their signaling cascade which is suggesting new treatment targets/approaches.

Summary

Recent insights from studies of VIP/PACAP and their receptors in both CNS disorders and inflammatory disorders suggest possible new treatment approaches. Elucidation of the exact roles of VIP/PACAP in these disorders and development of new therapeutic approaches involving these peptides have been limited by lack of specific pharmacological tools, and exact signaling mechanisms involved, mediating their effects. Reviewed here are recent insights from the elucidation of structural basis for VIP/PACAP receptor activation as well as the signaling cascades mediating their cellular effects(using results primarily from the study of their effects in cancer) which will likely lead to novel targets and treatment approaches in these diseases.

Keywords: VIP, PACAP, cancer, EGF/HER receptor transactivation, cAMP, phospholipase C

I. Introduction

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a 27 or 38 amino acid peptide which was isolated based on its ability to elevate cAMP in pituitary cells [1,2]. PACAP is structurally related (68% homology) to the 28 amino acid peptide, vasoactive intestinal peptide (VIP) which was isolated based on its ability to cause vasodilation [3]. VIP and PACAP, as well as their receptors are widely expressed in both the central nervous system as well as in peripheral tissues, particularly in neurons[4–6••]. In the central nervous system (CNS) PACAP and VIP are released from brain neurons and in a paracrine manner bind to receptors on adjacent neurons, astrocytes, microglia and/or peripheral inflammatory cells [5,7]. PACAP/ VIP interact with three different G-protein-coupled receptors: VPAC1, VPAC2 and PAC1, with both forms of PACAP having high affinity for all three, whereas VIP has high affinity only for VPAC1/VPAC2[4,5].When PACAP or VIP bind to the G protein-coupled receptors (GPCRs) VPAC1 or VPAC2, the cAMP is elevated leading to activation of protein kinase (PKA) and EPAC proteins [4–6••,8,9]. PACAP-27,−38 bind with high affinity to PAC1 resulting in activation of adenylyl cyclase and phospholipase (PLC) [4,5,8,10]. The PLC causes phosphatidylinositol (PI) turnover and the diacylglycerol (DAG) and inositol-1,4,5-trisphosphate (IP3) activate PKC and elevate cytosolic Ca2+, respectively[4,5,8,10].

VIP and PACAP in a number of cells including cancer cells often function in an autocrine manner wherein they are synthesized and released from the cell, and then bind to cell surface receptors on the same cell, and alter its behavior [11,12].

Both PACAP and VIP have reported to be involved in numerous physiological process as well as a large number of pathological processes[6••,7,13•,14•,15,16,17•,18•, 19], and in some cases, possible therapeutic roles proposed[18•,19–22,23•,24]. Recent reviews have focused on a number of these areas including : the role of VIP in the physiological/pathological processes in the gastrointestinal system [6••]; in neurodegenerative/neuroprotective disorders[13•]; in inflammatory/autoimmune disorders[7,24–26,27••,28,29]; in cancer[15,22,30,31]; in pulmonary disorders[32];in diabetes[26,33,34] as well as the importance of PACAP in various metabolic disorders[21]; in CNS neuroprotective/neurodegenerative disorders[14•,18•,19,21,35–37];in neuropsychiatric disorders[stress response, anxiety disorders, depression, post-traumatic stress disorder, schizophrenia, headache][18•,19,23•,38–42,43•,44•,45]; in addictive disorders[drugs, alcohol][46•,47,48•,49•,50•]; inflammatory disorders[7,19,24]; protective effects in renal injury/disease and other peripheral organs[GI tract, Respiratory system, cartilage/bone disorders, cardiovascular system][17•,51,52]; cancer[12,15,19,30,53•] and in diabetes[33,54–56].

In the above disorders, as well as most of the other disorders discussed in the accompanying paper (VIP/PACAP: PART II) that VIP/PACAP are involved in, the cellular basis of action/signaling cascades are not well studied or not clear. In this article (VIP/PACAP: Part 1) we briefly focus on recent insights into the pharmacology, cell biology, cellular basis of action/signaling of VIP/PACAP, primarily using cancer as a model system which has been studied in detailed.

II. VIP/PACAP receptors: pharmacology and cellular signaling

PACAP-27, PACAP-38 and PACAP-related peptide are derived from an ADCYAP1 precursor [preproPACAP) which contains 176 amino acids [4,5,57]. PACAP-27 or PACAP-38 bind with high affinity (nM range) to VPAC1 (457 amino acids), VPAC2 (438 amino acids) and PAC1 (468 amino acids), which are class B, secretin-like G protein coupled receptors (GPCRs) and interact with a stimulatory guanine nucleotide binding protein (Gs) resulting in activation of adenylyl cyclase elevating the cAMP[4,5,57]. PACAP-27 or PACAP-38 binding to PAC1 also results in interaction with Gq causing activation of phospholipase (PLC) resulting in the metabolism of PI [4,15,58•]. VIP is derived from a different precursor protein[preproVIP] which contains 170 amino acids[4,8]. In addition to VIP (28 amino acids), peptide histidine valine (42 amino acids) and peptide histidine methionine (27 amino acids) are also derived from this VIP precursor protein[4,8]. VIP binds with high affinity (nM range) to VPAC1 and VPAC2 but does not bind or activate PAC1, and thus differs from PACAPs which binds with high affinity to VPAC1, VPAC2 and PAC1. Because of this overlap, it can be difficult to establish which of the three receptors is mediating a given PACAP response(this will be discussed in more detail below).

VPAC1 has a large extracellular N-terminal (130 amino acids), 7 transmembrane (TM) domains, 3 extracellular (EC) loops, 3 intracellular (IC) loops and an intracellular C-terminal. Using photo-affinity labeling and modeling the C-terminal of VIP was found to interact with the N-terminal of VPAC1 [59] resulting in activation of VPAC1 and a change in the conformation of IC loop 3 activating Gs. In a recent study [60•] using cryo-electron microscopy it was found that PACAP-27 adopts an alpha helical conformation and engages VPAC1 with its N-terminal inserting into the ligand binding pocket at the transmembrane bundle core of the receptor interacting with all TM helices except TM4, and then couples to Gs.

In contrast to VPAC1/2, numerous PAC1 splice variants (SVs) frequently occur including both N-terminal and intracellular loop 3 variants that can differ in their signaling cascades [4,5,8,61–63]. Addition of a 28 amino acid segment to PAC1 null IC loop 3 results in the PAC1 hop SV[61]. Addition of a different 28 amino acid segment results in the formation of PAC1 hip SV[61]. Addition of both SV3 results in the formation of the PAC1 hip-hop SV[61]. The PAC1 SVs have altered ability to interact with Gq and cause PI turnover[61]. The PAC1 gene has 18 exons and deletion of exons 5, 6 or 4,5,6 reduces the size of the N-terminal by 7, 21 or 57 amino acids [64] and alternative slicing generates the different splice variants[4,5,8,61–63]. The PAC1 deletions have impaired ability to bind PACAP [65]. It remains to be determined if PAC1 alternative splicing can fine tune brain activity [63], however a number of studies in mammals and Zebrafish have implicated some of these spice variants in control of both body and cellular homeostasis[63].

Recent advances have been made in PAC1 structure and signal transduction. PAC1 has a 135 amino acid N-terminal, which contains antiparallel β-sheets that bind to the C-terminal of PACAP [66]. The N-terminal of PACAP interacts with TM5, TM6, TM7 which have an α-helix [66]. PAC1 has an open state (G4) and 3 closed transition states (G1–G3) and these structures can change on a time scale of milliseconds [67•]. During PAC1 movement, parts of TM6 and TM7 associate with ECL3, whereas parts of TM5 and TM6 associate with ICL3, which interacts with G proteins. H-bonds and electrostatic interactions are altered for Asn240, Arg199, Gln392 and Tyr241 of PAC1 during the conformation changes [21,67•]. The results indicate that major conformational changes occur during agonist binding to PAC1. Recently the cryo-EM structure of the human PAC1 receptor coupled to a heterotrimeric G protein was reported[58•]. The structure [58•] revealed that the TM1 helical domain plays a major role in PACAP recognition with aromatic residues of PACAP interacting with Y150,Y157 and Y161 in TM1; and that the PAC1R extracellular domains (ECD) function as an affinity trap and are not required for receptor activation.

PAC1 binds PACAP-27 (IC50 = 5 nM) or PACAP-38 (IC50 = 3 nM) but not VIP (IC50 = 500 nM) with high affinity [68]. The 61 amino acid peptide maxadilan binds with high affinity to PAC1, but not VPAC1 or VPAC2 but has little sequence homology to PACAP [69]. Also, (Iac1, Ala16,17, DLys28)(IAAD)PACAP-38 binds PAC1R with higher affinity and was more potent at elevating cAMP in cells containing PAC1 (EC50 = 0.05 nM) than cells containing VPAC1 (EC50 =1.5 nM) or VPAC2 (EC50 = 2.5 nM) [70] The results indicate that (IADD)PACAP-38 is 30–50 fold more potent at PAC1 than VPAC1 or VPAC2. There are no potent nonpeptide antagonists for PAC1 and the most widely used peptide antagonist PACAP (6–38) has low affinity[4,8,15,70].

The investigation of the exact role of VIP and PACAP in different pathological as well as physiological conditions has been hampered by the lack of high affinity, selective agonists and antagonists for the three receptor subtypes[VPAC 1/2, PAC1][15,16,21,58•,71–74]. At least two recent developments suggest this may change. First, is the detailed structural insights into the molecular basis for high affinity binding and activation of each of these receptors, briefly discussed above, will provide a firm basis for the development of selective ligands, as has been the case recently with a number of other G-protein coupled receptors[21,58•,60•,72,75]. In fact, recently, a number of investigators report various small molecule nonpeptide antagonists (hydrazides, PA compounds)[58•,76•], as well as identifying some lead compounds that may yield PAC1R or VPAC positive allosteric modulators or orthosteric/allosteric agonist/antagonists[21,77–79]. Secondly, recently there is increased use of monoclonal antibodies to specifically inactivate various targets in many diseases which have proven safe and effective[80–83]. For example, the peptide, CGRP has been shown to be important in the pathogenesis of migraine headaches[41,84,85,86•, 87]. Recently, the use of monoclonal antibodies to CGRP or its receptor have shown sustained efficacy in the prevention of migraine headaches and are well tolerated[41,88]. These have been so successfully thatcurrently four CGRP monoclonal antibodies have received FDA approval for the prevention of migraine: erenumab, fremanezumab, galcanezumab, and eptinezumab[89]. Recently, ALD1910[90••] a potent humanized neutralizing monoclonal antibody with a 4000-fold greater affinity for PACAP27/38 than VIP was described, which completely antagonized PACAPs activation of PAC1,VPAC1 and VPAC2, by binding to an epitope on PACAP and blocking its binding. ALD1910 should prove very useful for exploring the role of PACAP in various diseases and is being evaluated currently in a placebo-controlled trial for treatment of migraine, which will be discussed in more detail below.

III. VIP/PACAP receptors: Cancer

The important roles the VIP/PACAP system play in the growth, differentiation, and progression of a number of different neoplasms was reviewed in studies up to 2015 in the past[15,16,91,92]. In those reviews it was pointed out that many different neoplasms(particularly breast, lung, prostate, pancreas, central nervous system tumors, colon, gastric, urinary bladder) over-express either the VPAC1, VPAC2 or PAC1 receptors; that activation of these receptors affected tumor growth/differentiation; that there were increased insights into the cellular signaling cascades activated by these receptors that altered the neoplasms behavior and that these new insights were suggesting novel tumor treatments. In the following section more recent advances will be concentrated on with particular attention to novel insights from lung cancer studies which have provided a number of new insights into the cellular mechanisms by which VIP/PACAP receptor activation alters these neoplasm’s behavior, which may lead to novel treatments.

Lung cancer is a serious public health problem with over 150,000 deaths annually in the United States and 80–85% of cases are included in the nonsmall cell lung cancer(NSCLC) category. NSCLC is traditionally treated with combination chemotherapy; however, the 5-year survival rate is only 16% [93]. High densities of PACAP, VIP, VPAC1 and PAC1 but not VPAC2 mRNA are present in lung cancer cell lines [94]. With ligand binding studies,VPAC1 is found in 60% of lung cancers, while VAPC2 and PAC1R are uncommonly expressed at sufficient levels to be detected[95]. PACAP immunoreactivity is present in many lung cancer biopsy specimens [96]. In contrast to NSCLC, PAC1 has been detected in endometrial, breast, colon, liver, neuroblastoma, pancreatic and prostate cancers [20,31,95,97]. Similar to NSCLC, VPAC1 are frequently present in breast, colon, lung, liver, pancreas prostate, stomach and urinary bladder cancer biopsy specimens [95], whereas VPAC2 is less frequently found in neoplasms, however some tumors such as leiomyomas express predominantly VPAC2[95].

The addition of VIP or PACAP stimulates the clonal growth of NSCLC cells [98]. In contrast, VIP hybrid (VPAC1/ VPAC2 antagonist) or PACAP (6–38) (PAC1 antagonist) inhibit the growth of NSCLC cells [99] In addition to elevating second messengers (VIPR-cAMP,PAC1-cAMP,Phospholipase C [PLC]-Ca/phosphoinositides/PKC), VIP or PACAP cause phosphorylation of a number of proteins that have important growth effects. PACAP addition to NSCLC cells stimulates tyrosine phosphorylation of focal adhesion kinase (FAK) and proline-rich tyrosine kinase (PYK) which interact with the actin cytoskeleton and Rho family GTPases, respectively [99,100]. The ability of PACAP to increase FAK and PYK phosphorylation was impaired by PP2 (Src inhibitor), U73122 (PLC inhibitor) and PACAP(6–38). FAK and PYK play a role in cancer metastasis. Also, PACAP addition to NSCLC cells increased the tyrosine phosphorylation of the epidermal growth factor receptor (EGFR), a receptor tyrosine kinase (RTK) [98,101].

The mechanism by which PAC1 regulates EGFR transactivation is fairly complex [53•,98,102,103]. PLCγ is tyrosine phosphorylated after PAC1 binds agonist resulting in metabolism of PIP2 to IP3 (increases Ca2+) and DAG (activates PKC) leading to the phosphorylation of Src. Pro-transforming growth factorα (TGFα) is metabolized by matrix metalloproteinases (MMP) resulting in the secretion of TGFα, which binds to the EGFR. The EGFR forms homodimers resulting in the activation of the ERK pathway. RAS phosphorylates Raf, which phosphorylates MEK, which phosphorylates ERK which activates the serum response factor leading to increased cellular proliferation. Also, reactive oxygen species (ROS) are required for the EGFR to increase tyrosine phosphorylation of protein substrates. The ability of PACAP to increase EGFR transactivation is impaired by PACAP(6–38), PP2 (Src inhibitor), GM6001 (MMP inhibitor), N-acetyl cysteine (antioxidant), TGFα mAb (neutralizes TGFα) and gefitinib (Tyrosine kinase inhibitor[TKI]). In addition to tyrosine phosphorylation of protein substrates, the EGFR can be auto-phosphorylated at Y974, Y992, Y1045, Y1068, Y1086, Y1114, Y1148 and Y1173. The transactivation process is very rapid taking 1 min and it takes 2 min for ERK to be phosphorylated. PACAP can increase cAMP, however, addition of the PKA inhibitor H89, has little effect on transactivation, supporting the conclusion that it is mediated by activation of PLC. In summary, PACAP addition to NSCLC cells causes EGFR transactivation in a PLC-dependent manner that requires ligands such as TGFα.

In addition to EGFR forming homodimers with another EGFR, activated EGFR can from heterodimers with HER2 [53•,103,104]. PACAP addition to NSCLC cells results in the phosphorylation of HER2 at Y1005, Y1023, Y1139, Y1196, Y1222 and Y1248. and ERK is phosphorylated leading to an increase in nuclear oncogene expression and proliferation. The phosphorylation of HER2 can be blocked by trastuzumab (mAb) or lapatinib (EGFR and HER2 TKI) and diphenylene iodonium (DPI). DPI is an inhibitor of NADPH (Nox) and Duox enzymes. Surprisingly, many of the 10 NSCLC cells examined had mRNA for Nox1, Nox2, Nox3, Nox4, Nox5, Duox1 and Duox2. DPI is a universal inhibitor for all of these enzymes. Addition of PACAP to NSCLC increased ROS and this increase was inhibited by DPI. Also, DPI inhibited the growth of NSCLC cells.

Recent studies show that in lung cancer cells activation of PAC1 and other G-protein coupled receptors can stimulate EGFR and HER2 can also form heterodimers with HER3 [103,105]. PACAP addition to NSCLC cells can result in the phosphorylation of HER3 at Y1054, Y1197, Y1199, Y1222, Y1260, Y1262, Y1276, Y1289 and Y1328. The phosphorylation of HER3 caused by addition of PACAP to NSCLC cells was impaired by PACAP(6–38), and mAb 3481 (HER3 blocker). PI3K is activated leading to the phosphorylation of AKT increasing the proliferation and survival of NSCLC cells. The proliferation of NSCLC cells was increased by NRG-1, a growth factor for HER3, and PACAP but inhibited by PACAP(6–38), gefitinib, trastuzumab and mAb 3481. The NSCLC growth was strongly inhibited by addition of both PACAP(6–38) and gefitinib. These results demonstrate the most complete inhibition of transactivation of the EGFR/HER family in NSCLC cells is to use a GPCR antagonist and a tyrosine kinase inhibitor.

In lung cancer cells, despite the presence of VPAC1, VIP has little effect on transactivation of the EGFR, HER2 and HER3. This is in contrast to breast cancer cells, in which VIP increased the transactivation of the EGFR and HER2 [104,106]. In these cells, the increase in EGFR and HER2 transactivation was impaired by growth hormone-releasing hormone analog (JV-1–53) and siRNA against VPAC1 [104,106].The transactivation of the EGFR by VIP was blocked also by H-89, a PKA inhibitor [107]. In the colonic adenocarcinoma cell line, T84 cells, the transactivation of the EGFR and HER2 caused by VPAC1 was impaired by Src and MMP inhibitors [108] the transactivation is ligand dependent. A recent study [109] demonstrates a new novel cascade of EGFR transactivation by VIP in colonic adenocarcinoma cells[CACO cells]. Activation of VPAC1 increases PKA activity which stimulated the phosphorylation of naked cuticle homolog 2 (NDK2) which in turn stimulated the cell-surface delivery of TGF-α for EGFR transactivation [109]. NDK2 is phosphorylated by PKA utilizing scaffold A-kinase anchoring protein 12 (AKAP12). These results indicate that there are differences in the way in which PAC1 and VPAC1 regulate the ligand-dependent transactivation of the EGFR and HER2 in different cancer cells.

PACAP addition to the pheochromocytoma cell line, PC12 cells increases TrkA tyrosine phosphorylation in a ligand (NGF) independent manner which induces trophic effects on the cell which can result in a neuroprotective effect. VIP-stimulated transactivation of TrkA occurred hours after the addition of PACAP to PC12 cells [110]. The increased cAMP and the increase in TrkA phosphorylation caused by PACAP addition was impaired H89, a PKA inhibitor. The increase in TrkA and AKT phosphorylation caused by PACAP was impaired by K252a, a TKI, and PP1, a Src inhibitor. PACAP activated cAMP/exchange protein (Epac) in a cAMP dependent manner [111]. The PAC1 mediated TrkA phosphorylation is essential for EPAC to activate Rit GTPase leading to PC12 cellular differentiation.

The elucidation of these novel signaling cascades activated by VIP/PACAP in both normal cells and cancer cells may lead to novel therapeutic approaches. As discussed in the other sections of this review, VIP/PACAP are involved in numerous both physiological and pathological processes such as having potent anti-inflammatory activity, neuroprotective effects, etc., however the cellular signaling mechanism in most of these processes remains unknown, whereas the detailed studies in especially cancer cells are providing important insights into the cellular signaling cascades activated by the peptides. The elucidation of this cascades will likely identify important therapeutic targets for disorders in which VIP/PACP system play an important role.

IV. Conclusions

The recent insights into the pharmacology, cell signaling and molecular basis for activation/binding affinity interaction for VPAC and PAC1 receptors has identified new possible cellular targets, have provided insights raising the likelihood of the development of selective nonpeptide ligands, and this coupled with the development of neutralizing monoclonal antibodies for PACAP and VIP are increasing the likelihood of VIP/PACAP based therapeutic approaches in various disorders becoming a distinct possibility.

KEY POINTS.

  • VIP/PACAP and their receptors are involved in numerous physiological/pathological processes

  • They have important roles in a number of cancers

  • Their exact role in various physiological/pathological processes has been impeded by the lack of potent, specific receptor agonists/antagonists

  • Recent studies show increasing insights into their molecular basis of receptor activation which will likely facilitate the increased identification of small molecule receptor ligands(agonists/antagonists)

  • Recent insights into the signaling cascades mediated by VPAC1/2 and PAC1 activation in such diseases as cancer, and the development of neutralizing monoclonal antibodies for VIP/PACAP are increasing the likelihood of the development of novel therapeutic approaches in numerous disorders.

Financial support

This research was partially supported by the intramural program of NIDDK/NCI of the NIH.

Footnotes

Conflicts of Interest

None

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