Human Vasoactive Intestinal Peptide Receptor 2 - GPCR extracellular domain

About this structure

IPR1 and 2 belong to the class II subfamily of the seven-transmembrane (7TM) G-protein-coupled receptor (GPCR) superfamily. The Class II GPCRs are characterised by a 100 to 200 residue amino terminal extracellular domain with 3 conserved disulphide bonds. VIPR1 and 2, also termed the VPAC1 and VPAC2 receptors respectively, are 49% conserved on the amino acid level and serve as receptors for two related neuropeptides, the vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase-activating polypeptide (PACAP) (Laburthe et al., 2002).

The vasoactive intestinal peptide (VIP) is a neuropeptide and endocrine hormone with wide ranging effects on the gut, brain and heart. In the digestive system VIP controls secretion of water and electrolytes into the gut, secretion of water into pancreatic juice and bile, relaxation of smooth muscle in parts of the gut and regulation of gastric acid and pepsinogen secretion. In the brain VIP acts as a neuropeptide, passing signals between neurons, particularly those associated with the Suprachiasmatic nuclei, the region responsible for the brain's timekeeping function, or circadian rhythms. Knockout mice for the VIP receptor VIPR2 established the essential role for this receptor in controlling the maintenance of circadian rhythm and further analysis demonstrated that VIPR2 is not only essential for synchronisation of circadian pacemakers in the suprachiasmatic nuclei (SCN) but is also necessary to maintain the molecular timekeeping within individual SCN neurons and to regulate the excitability of SCN neurons (Harmar, 2003), (Maywood et al., 2007). In addition, mice lacking VIPR2 show increased delayed type hypersensitivity but depressed immediate-type hypersensitivity demonstrating the involvement of VIPR2 in regulation of T-cell function (Goetzl et al., 2001). VIPR2 also regulates insulin secretion, growth, lipolysis and male reproductive functions as demonstrated by a conditional knockout lacking exon 8-10 of VIPR2 (Asnicar et al., 2002). VIP receptor manipulation is used in treatments for several diseases: VIPR2 agonists are used as bronchodilators in asthma and are considered for the treatment of Type II diabetes (Schmidt et al., 2001), (Pan et al., 2007). VIPR2 has been suggested as a target for antiinflammatory agents in rheumatoid arthritis (Gomariz et al., 2006). Overexpression of VIPR2 has been described in central primitive neuroectodermal tumours as well as gastrointestinal tumours. Overproduction of VIP in pancreatic tumours (VIPomas) results in chronic diarrhoea. Polymorphisms in VIPR2 may affect gastrointestinal symptoms and stereotypical behaviours in autism (Vaudry et al., 2009), (Asano et al., 2001). VIP is also involved in heart function, causing coronary vasodilation and it is therefore being investigated as a possible treatment for heart failure.

Here we describe the structure of VIPR2 extracellular domain at 2.1 Å. In common with the other class B GPCR extracellular domains the VIPR2 has an N-terminal α-helix packed against a 2-stranded β-sheet and a 3-stranded β-sheet. The structure is held together by three disulphide bonds. Although this is an unliganded structure, crystallised without peptide bound, it is known from related crystal and NMR structures that the C-terminus of the peptide hormones usually bind in the region of loops 2 and 4 (Parthier, et al., 2009). The N-terminus of the VIP would then extend into the C-terminal domain of the receptor, the seven-transmembrane GPCR domain, thus transmitting the signal across the cell membrane via the G-α GTPase to adenylate cyclase or phospholipase C.

References

1. Asano, E., Kuivaniemi, H., Huq, A.H., Tromp, G., Behen, M., Rothermel, R., Herron, J., and Chugani, D.C. (2001). A study of novel polymorphisms in the upstream region of vasoactive intestinal peptide receptor type 2 gene in autism. J Child Neurol 16, 357-363.
2. Asnicar, M.A., Koster, A., Heiman, M.L., Tinsley, F., Smith, D.P., Galbreath, E., Fox, N., Ma, Y.L., Blum, W.F., and Hsiung, H.M. (2002). Vasoactive intestinal polypeptide/pituitary adenylate cyclase-activating peptide receptor 2 deficiency in mice results in growth retardation and increased basal metabolic rate. Endocrinology 143, 3994-4006.
3. Goetzl, E.J., Voice, J.K., Shen, S., Dorsam, G., Kong, Y., West, K.M., Morrison, C.F., and Harmar, A.J. (2001). Enhanced delayed-type hypersensitivity and diminished immediate-type hypersensitivity in mice lacking the inducible VPAC(2) receptor for vasoactive intestinal peptide. Proc Natl Acad Sci U S A 98, 13854-13859.
4. Gomariz, R.P., Juarranz, Y., Abad, C., Arranz, A., Leceta, J., and Martinez, C. (2006). VIP-PACAP system in immunity: new insights for multitarget therapy. Ann N Y Acad Sci 1070, 51-74.
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8. Pan, C.Q., Li, F., Tom, I., Wang, W., Dumas, M., Froland, W., Yung, S.L., Li, Y., Roczniak, S., Claus, T.H., et al. (2007). Engineering novel VPAC2-selective agonists with improved stability and glucose-lowering activity in vivo. J Pharmacol Exp Ther 320, 900-906.
9. Schmidt, D.T., Ruhlmann, E., Waldeck, B., Branscheid, D., Luts, A., Sundler, F., and Rabe, K.F. (2001). The effect of the vasoactive intestinal polypeptide agonist Ro 25-1553 on induced tone in isolated human airways and pulmonary artery. Naunyn Schmiedebergs Arch Pharmacol 364, 314-320.
10. Vaudry, D., Falluel-Morel, A., Bourgault, S., Basille, M., Burel, D., Wurtz, O., Fournier, A., Chow, B.K., Hashimoto, H., Galas, L., et al. (2009). Pituitary adenylate cyclase-activating polypeptide and its receptors: 20 years after the discovery. Pharmacol Rev 61, 283-357.
11. Parthier, C., Reedtz-Runge, S., Rudolph, R. and Stubbs, M.T.,(2009) Passing the baton in class B GPCRs: peptide hormone activation via helix induction? TIBS, 34. 6, 303-310.