The many faces of VIP in neuroimmunology: a cytokine rather a neuropeptide?

10 pages, 3 figures.-- PMID: 15333575 [PubMed].Neuroimmunomodulation has experienced an explosive growth not only in basic research, but expanding to the point that prospective clinical research could be now a reality. A crucial factor for the functioning of this intimate bidirectional network was the demonstration that the immune and neuroendocrine systems speak a mutual biochemical language. This implies 1) production of neuroendocrine hormones and neuropeptides by immune cells and of cytokines by neuroendocrine cells; 2) evidence for shared receptors on cells of the immune and neuroendocrine systems; 3) effect of neuroendocrine mediators on immune functions; and 4) effect of cytokines on the neuroendocrine system. This reduces traditional differences between neurotransmitters, hormones, and immune mediators and raises the following question: what can we now regard as immune or neuroendocrine? Vasoactive intestinal peptide (VIP) is one example of this paradigm. VIP has traditionally been classified as a neuropeptide/neurotransmitter based in its capacity to mediate and regulate neuronal functions. Recent work has demonstrated that VIP is produced by T cells, especially Th2 cells, and that through specific receptors it exerts immunological functions typically ascribed to Th2 cytokines in nervous and immune systems. Here, we postulate that instead of a neuropeptide, VIP could be fully considered a type 2 cytokine with a key role in neuroimmunology.This study was supported by extramural grants from the Instituto de Salud Carlos III, Fondo de Investigacion Sanitaria, Spanish Ministry of Health (PI 030359 to D.P and PI 030526 to M.D.), from La Caixa Foundation (NE-03-009 to M.D) and from the European Union 6th Framework Grants Program (FP6-006380 to D.P).Peer reviewe

Potential PET Ligands for Imaging of Cerebral VPAC and PAC Receptors: Are Non-Peptide Small Molecules Superior to Peptide Compounds?

Pituitary adenylate cyclase activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) have been known for decades to mediate neuroendocrine and vasodilative actions via G-protein-coupled receptors of Class B. These are targets of imaging probes for positron emission tomography (PET) or single photon emission tomography (SPECT) in tumor diagnostics and tumor grading. However, they play only a subordinate role in the development of tracers for brain imaging. Difficulties in development of non-peptide ligands typical for cerebral receptors of PACAP and VIP are shared by all members of Class B receptor family. Essential landmarks have been confirmed for understanding of structural details of Class B receptor molecular signalling during the last five years. High relevance in the explanation of problems in ligand development for these receptors is admitted to the large N-terminal ectodomain markedly different from Class A receptor binding sites and poorly suitable as orthosteric binding sites for the most small-molecule compounds. The present study is focused on the recently available receptor ligands for PAC1, VPAC1 and VPAC2 receptors as well as potential small-molecule lead structures suitable for use in PET or SPECT. Recently, biaryl, cyanothiophene and pentanamide structures with affinities in nM-range have been proposed as non-peptide ligands at VPAC1 and VPAC2 receptors. However, most of these ligands have been classified as non-competitive related to the orthosteric binding site of endogenous peptide ligands of VPAC receptors. For PAC1 receptors have been identified hydrazide compounds for which an inhibitory and potentially competitive mechanism of receptor binding has been postulated based on molecular docking studies

The role of specific receptor domains in signal transduction by the VIP2 receptor

Receptors for the neuropeptides VIP and P ACAP belong to a novel sub-family of G protein-coupled receptors, the secretin/ calcitonin/ parathyroid hormone receptor family. The rat VIP2 receptor was recently cloned in this laboratory and the present project was carried out to characterise the signalling mechanisms used by this receptor and define the role of crucial receptor domains. These studies have primarily involved the transient expression of receptors in host cells. The results demonstrated for the first time that both the VIP1 and VIP2 receptors can stimulate phospholipase C (PLC) in addition to adenylate cyclase (AC) and that this stimulation occurs by a pertussis toxin(PTx)-sensitive mechanism. Correspondingly, GTP,.S modulation of ligand-binding to the VIP2 receptor in COS 7 cell membranes was shown to be partially PTx-sensitive, suggesting an interaction of the receptor with a PTx-sensitive G protein. An epitope-tagged human VIP2 receptor was expressed in COS 7 cells and imrnunoprecipitated with its associated G proteins for Western-blotting studies. Immunoreactivity for Gaq, Ga5 and a member of the G<Xif o/ t/ z family, other than Gan or G<Xi2, appeared to be associated with the receptor. The use of specific calcium channel blockers identified a role for receptor-mediated calcium influx in VIP2 receptormediated PLC stimulation. The P ACAP and VIP2 receptors contain many common structural features but have their own distinct pharmacological profiles. The function of specific domains of the VIP2 receptor was investigated by creating P ACAP /VIP2 receptor chimaerics and C-terminal truncations of the Vll'2 receptor. These constructs allowed identification of the primary region of the receptor responsible for ligand-binding and the probable site of interaction with a PTx-sensitive G protein and also assessment of any contribution of the C-terminus to AC and PLC stimulation. A number of further studies were carried out on native receptors. The signalling pathways activated by the endogenous Vll'2 receptor in the Gfl3 rat pituitary tumour cell line were investigated. Consistent with previous evidence that a Vll' receptor in other cells can stimulate nitric oxide production, VIP2 receptor-mediated stimulation of nitric oxide synthase, PLC and AC was demonstrated in GHJ cells. As a result of reports describing the effects of VIP and P ACAP on cerebral blood flow the Reverse Transcriptase-Polymerase Chain Reaction technique was used to determine the type of VIP receptor present in rat cerebral microvessels

Enter the Dragon: The Dynamic and Multifunctional Evolution of Anguimorpha Lizard Venoms

While snake venoms have been the subject of intense study, comparatively little work has been done on lizard venoms. In this study, we have examined the structural and functional diversification of anguimorph lizard venoms and associated toxins, and related these results to dentition and predatory ecology. Venom composition was shown to be highly variable across the 20 species of Heloderma, Lanthanotus, and Varanus included in our study. While kallikrein enzymes were ubiquitous, they were also a particularly multifunctional toxin type, with differential activities on enzyme substrates and also ability to degrade alpha or beta chains of fibrinogen that reflects structural variability. Examination of other toxin types also revealed similar variability in their presence and activity levels. The high level of venom chemistry variation in varanid lizards compared to that of helodermatid lizards suggests that venom may be subject to different selection pressures in these two families. These results not only contribute to our understanding of venom evolution but also reveal anguimorph lizard venoms to be rich sources of novel bioactive molecules with potential as drug design and development lead compounds

VIP and PACAP receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Vasoactive Intestinal Peptide Receptors [64, 65]) are activated by the endogenous peptides VIP, PACAP-38, PACAP-27, peptide histidine isoleucineamide (PHI), peptide histidine methionineamide (PHM) and peptide histidine valine (PHV). VPAC1 and VPAC2 receptors display comparable affinity for the PACAP peptides, PACAP-27 and PACAP-38, and VIP, whereas PACAP-27 and PACAP-38 are >100 fold more potent than VIP as agonists of most isoforms of the PAC1 receptor. However, one splice variant of the human PAC1 receptor has been reported to respond to PACAP-38, PACAP-27 and VIP with comparable affinity [29]. PG 99-465 [115] has been used as a selective VPAC2 receptor antagonist in a number of physiological studies, but has been reported to have significant activity at VPAC1 and PAC1 receptors [35]. The selective PAC1 receptor agonist maxadilan, was extracted from the salivary glands of sand flies (Lutzomyia longipalpis) and has no sequence homology to VIP or the PACAP peptides [116]. Two deletion variants of maxadilan, M65 [180] and Max.d.4 [117] have been reported to be PAC1 receptor antagonists, but these peptides have not been extensively characterised

VIP and PACAP receptors in GtoPdb v.2023.1

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Vasoactive Intestinal Peptide Receptors [65, 66]) are activated by the endogenous peptides VIP, PACAP-38, PACAP-27, peptide histidine isoleucineamide (PHI), peptide histidine methionineamide (PHM) and peptide histidine valine (PHV). VPAC1 and VPAC2 receptors display comparable affinity for the PACAP peptides, PACAP-27 and PACAP-38, and VIP, whereas PACAP-27 and PACAP-38 are &gt;100 fold more potent than VIP as agonists of most isoforms of the PAC1 receptor. However, one splice variant of the human PAC1 receptor has been reported to respond to PACAP-38, PACAP-27 and VIP with comparable affinity [30]. PG 99-465 [117] has been used as a selective VPAC2 receptor antagonist in a number of physiological studies, but has been reported to have significant activity at VPAC1 and PAC1 receptors [36]. The selective PAC1 receptor agonist maxadilan, was extracted from the salivary glands of sand flies (Lutzomyia longipalpis) and has no sequence homology to VIP or the PACAP peptides [118]. Two deletion variants of maxadilan, M65 [183] and Max.d.4 [119] have been reported to be PAC1 receptor antagonists, but these peptides have not been extensively characterised