Adhesion Class GPCRs: Introduction

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The Adhesion class of GPCRs comprises 33 members in humans with a broad tissue distribution in cells of the reproductive tract, neurons, leukocytes, gut and a variety of tumors. Adhesion GPCRs are highly evolutionary conserved, found throughout metazoans and in single-celled colony forming and unicellular organisms. The extracellular subunits of Adhesion GPCRs can be exceptionally long and contain a variety of structural domains that are known for the ability to facilitate cell and matrix interactions. Intramolecular processing at a GPCR-proteolytic site (GPS) proximal to the first transmembrane helix can give rise to a membrane-spanning and an extracellular subunit, which subsequently reassociate non-covalently, resulting in expression of a heterodimeric receptor at the cell surface. Ligand profiles and in vitro studies have indicated a role of Adhesion GPCRs in cell adhesion and migration. The function of Adhesion GPCRs may relate to the proper positioning of cells in a variety of organ systems. Growing evidence implies a role of Adhesion GPCRs in tumor cell metastasis, gut functions as well as in the CNS. In 2011, a consortium of international scientists was established to facilitate research into of the physiological and pathological functions of Adhesion GPCRs (http://www.adhesiongpcr.org).

Gene nameK/O mouse Y/NPhenotype Y/NPhenotype descriptionReference
BAI1Non/a  
BAI2YesYesAntidepressant-like behaviour[16]
BAI3Non/a  
CD97YesYesAmelioration of symptoms in experimentally-induced arthritis[8]
CD97YesYesImproved anti-bacterial host defense, mild granulocytosis[25-26,29]
LPHN1YesYesAbnormal female nurturing [23]
LPHN3YesYesHyperactivity, increased sensitivity to the stimulant effects of cocaine [28]
CELSR1YesYesCompromised neural migration in the hindbrain[17]
CELSR1YesYesDefects in orientation of hair outgrowth[18]
CELSR2YesYesImpaired ependymal ciliogenesis[22]
CELSR2YesYesDefects in the migration of hindbrain neurons [17]
CELSR2YesYesReduced quiescence of haemopoetic stem cells[20]
CELSR3YesYesImparied axonal tract development [21]
CELSR3YesYesDefects in pancreatic Beta-cell generation [3]
CELSR3YesYesDefects in tangential cortical interneuron migration[32]
CELSR3YesYesDefects in anterior-posterior axon tract organisation in the brainstem.[7]
CELSR3YesYesDysfunction of hippocampal connectivity and maturation and forebrain wiring[6,33-34]
ELTD1YesYesAugmented cardiac hypertrophy in response to pressure overload[30]
EMR1YesYesFailure in peripheral immune tolerance [12,19]
EMR2Non/a  
EMR3Non/a  
EMR4Non/a  
GPR56YesYesNeuronal ectopia in the cerebral cortex[9,11]
GPR56YesYesMalformation of the male gonad resulting in impaired fertility with defects originate during embryogenesis[2]
GPR64YesYesInfertility in male mice [5]
GPR97YesNo  
GPR98YesYesImparied cochlea function resulting from imparied development in stereocilia[31]
GPR98YesYesDecreased bone mineral density, mechanical fragility of cortical bone[24]
GPR98YesYesAbsence of usherin, vezatin and whirlin at the stereocilia base of the cochlea resulting in abnormal mechanoelectrical transduction currents[13]
GPR110Non/a  
GPR111YesNo  
GPR112Non/a  
GPR113Non/a  
GPR114Non/a  
GPR115YesNo  
GPR116YesYesExacerbated glucose intolerance and insulin resistance, hyperlipidemia, ectopic lipid accumulation, reduced adipocyte size, disregulated adipokine expression in adipocyte[15]
GPR123Non/a  
GPR124YesYesFetal or perinatal lethality. CNS-specific angiogenesis arrest in forebrain and neural tube[10]
GPR124YesYesAbnormal angiogenesis of the brain and spinal chord[4]
GPR124YesYesAbnormal vascular phenotype including delayed vascular penetration; defects in palate and lung development[1]
GPR125Non/a  
GPR126YesYesImpaired organogenesis, circulatory failure resulting in embryonic lethality[27]
GPR126YesYesAbsence of nerve myelination and other verve development defects resulting in some embryonic lethality[14]
GPR128Non/a  
GPR133Non/a  
GPR144Non/a  
GPR157Non/a  
LPHN2Non/a 

References

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1. Anderson KD, Pan L, Yang XM, Hughes VC, Walls JR, Dominguez MG, Simmons MV, Burfeind P, Xue Y, Wei Y et al.. (2011) Angiogenic sprouting into neural tissue requires Gpr124, an orphan G protein-coupled receptor. Proc. Natl. Acad. Sci. U.S.A., 108 (7): 2807-12. [PMID:21282641]

2. Chen G, Yang L, Begum S, Xu L. (2010) GPR56 is essential for testis development and male fertility in mice. Dev. Dyn., 239 (12): 3358-67. [PMID:20981830]

3. Cortijo C, Gouzi M, Tissir F, Grapin-Botton A. (2012) Planar cell polarity controls pancreatic Beta cell differentiation and glucose homeostasis. Cell Rep, 2 (6): 1593-606. [PMID:23177622]

4. Cullen M, Elzarrad MK, Seaman S, Zudaire E, Stevens J, Yang MY, Li X, Chaudhary A, Xu L, Hilton MB et al.. (2011) GPR124, an orphan G protein-coupled receptor, is required for CNS-specific vascularization and establishment of the blood-brain barrier. Proc. Natl. Acad. Sci. U.S.A., 108 (14): 5759-64. [PMID:21421844]

5. Davies B, Baumann C, Kirchhoff C, Ivell R, Nubbemeyer R, Habenicht UF, Theuring F, Gottwald U. (2004) Targeted deletion of the epididymal receptor HE6 results in fluid dysregulation and male infertility. Mol. Cell. Biol., 24 (19): 8642-8. [PMID:15367682]

6. Feng J, Xu Y, Wang M, Ruan Y, So KF, Tissir F, Goffinet A, Zhou L. (2012) A role for atypical cadherin Celsr3 in hippocampal maturation and connectivity. J. Neurosci., 32 (40): 13729-43. [PMID:23035085]

7. Fenstermaker AG, Prasad AA, Bechara A, Adolfs Y, Tissir F, Goffinet A, Zou Y, Pasterkamp RJ. (2010) Wnt/planar cell polarity signaling controls the anterior-posterior organization of monoaminergic axons in the brainstem. J. Neurosci., 30 (47): 16053-64. [PMID:21106844]

8. Hoek RM, de Launay D, Kop EN, Yilmaz-Elis AS, Lin F, Reedquist KA, Verbeek JS, Medof ME, Tak PP, Hamann J. (2010) Deletion of either CD55 or CD97 ameliorates arthritis in mouse models. Arthritis Rheum., 62 (4): 1036-42. [PMID:20131275]

9. Koirala S, Jin Z, Piao X, Corfas G. (2009) GPR56-regulated granule cell adhesion is essential for rostral cerebellar development. J. Neurosci., 29 (23): 7439-49. [PMID:19515912]

10. Kuhnert F, Mancuso MR, Shamloo A, Wang HT, Choksi V, Florek M, Su H, Fruttiger M, Young WL, Heilshorn SC et al.. (2010) Essential regulation of CNS angiogenesis by the orphan G protein-coupled receptor GPR124. Science, 330 (6006): 985-9. [PMID:21071672]

11. Li S, Jin Z, Koirala S, Bu L, Xu L, Hynes RO, Walsh CA, Corfas G, Piao X. (2008) GPR56 regulates pial basement membrane integrity and cortical lamination. J. Neurosci., 28 (22): 5817-26. [PMID:18509043]

12. Lin HH, Faunce DE, Stacey M, Terajewicz A, Nakamura T, Zhang-Hoover J, Kerley M, Mucenski ML, Gordon S, Stein-Streilein J. (2005) The macrophage F4/80 receptor is required for the induction of antigen-specific efferent regulatory T cells in peripheral tolerance. J. Exp. Med., 201 (10): 1615-25. [PMID:15883173]

13. Michalski N, Michel V, Bahloul A, Lefèvre G, Barral J, Yagi H, Chardenoux S, Weil D, Martin P, Hardelin JP et al.. (2007) Molecular characterization of the ankle-link complex in cochlear hair cells and its role in the hair bundle functioning. J. Neurosci., 27 (24): 6478-88. [PMID:17567809]

14. Monk KR, Oshima K, Jörs S, Heller S, Talbot WS. (2011) Gpr126 is essential for peripheral nerve development and myelination in mammals. Development, 138 (13): 2673-80. [PMID:21613327]

15. Nie T, Hui X, Gao X, Li K, Lin W, Xiang X, Ding M, Kuang Y, Xu A, Fei J et al.. (2012) Adipose tissue deletion of Gpr116 impairs insulin sensitivity through modulation of adipose function. FEBS Lett., 586 (20): 3618-25. [PMID:22971422]

16. Okajima D, Kudo G, Yokota H. (2011) Antidepressant-like behavior in brain-specific angiogenesis inhibitor 2-deficient mice. J Physiol Sci, 61 (1): 47-54. [PMID:21110148]

17. Qu Y, Glasco DM, Zhou L, Sawant A, Ravni A, Fritzsch B, Damrau C, Murdoch JN, Evans S, Pfaff SL, Formstone C, Goffinet AM, Chandrasekhar A, Tissir F. (2010) Atypical cadherins Celsr1-3 differentially regulate migration of facial branchiomotor neurons in mice. J. Neurosci., 30 (28): 9392-401. [PMID:20631168]

18. Ravni A, Qu Y, Goffinet AM, Tissir F. (2009) Planar cell polarity cadherin Celsr1 regulates skin hair patterning in the mouse. J. Invest. Dermatol., 129 (10): 2507-9. [PMID:19357712]

19. Schaller E, Macfarlane AJ, Rupec RA, Gordon S, McKnight AJ, Pfeffer K. (2002) Inactivation of the F4/80 glycoprotein in the mouse germ line. Mol. Cell. Biol., 22 (22): 8035-43. [PMID:12391169]

20. Sugimura R, He XC, Venkatraman A, Arai F, Box A, Semerad C, Haug JS, Peng L, Zhong XB, Suda T et al.. (2012) Noncanonical Wnt signaling maintains hematopoietic stem cells in the niche. Cell, 150 (2): 351-65. [PMID:22817897]

21. Tissir F, Bar I, Jossin Y, De Backer O, Goffinet AM. (2005) Protocadherin Celsr3 is crucial in axonal tract development. Nat. Neurosci., 8 (4): 451-7. [PMID:15778712]

22. Tissir F, Qu Y, Montcouquiol M, Zhou L, Komatsu K, Shi D, Fujimori T, Labeau J, Tyteca D, Courtoy P, Poumay Y, Uemura T, Goffinet AM. (2010) Lack of cadherins Celsr2 and Celsr3 impairs ependymal ciliogenesis, leading to fatal hydrocephalus. Nat. Neurosci., 13 (6): 700-7. [PMID:20473291]

23. Tobaben S, Südhof TC, Stahl B. (2002) Genetic analysis of alpha-latrotoxin receptors reveals functional interdependence of CIRL/latrophilin 1 and neurexin 1 alpha. J. Biol. Chem., 277 (8): 6359-65. [PMID:11741895]

24. Urano T, Shiraki M, Yagi H, Ito M, Sasaki N, Sato M, Ouchi Y, Inoue S. (2012) GPR98/Gpr98 gene is involved in the regulation of human and mouse bone mineral density. J. Clin. Endocrinol. Metab., 97 (4): E565-74. [PMID:22419726]

25. Veninga H, Becker S, Hoek RM, Wobus M, Wandel E, van der Kaa J, van der Valk M, de Vos AF, Haase H, Owens B et al.. (2008) Analysis of CD97 expression and manipulation: antibody treatment but not gene targeting curtails granulocyte migration. J. Immunol., 181 (9): 6574-83. [PMID:18941248]

26. Veninga H, Hoek RM, de Vos AF, de Bruin AM, An FQ, van der Poll T, van Lier RA, Medof ME, Hamann J. (2011) A novel role for CD55 in granulocyte homeostasis and anti-bacterial host defense. PLoS ONE, 6 (10): e24431. [PMID:21984892]

27. Waller-Evans H, Prömel S, Langenhan T, Dixon J, Zahn D, Colledge WH, Doran J, Carlton MB, Davies B, Aparicio SA et al.. (2010) The orphan adhesion-GPCR GPR126 is required for embryonic development in the mouse. PLoS ONE, 5 (11): e14047. [PMID:21124978]

28. Wallis D, Hill DS, Mendez IA, Abbott LC, Finnell RH, Wellman PJ, Setlow B. (2012) Initial characterization of mice null for Lphn3, a gene implicated in ADHD and addiction. Brain Res., 1463: 85-92. [PMID:22575564]

29. Wang T, Tian L, Haino M, Gao JL, Lake R, Ward Y, Wang H, Siebenlist U, Murphy PM, Kelly K. (2007) Improved antibacterial host defense and altered peripheral granulocyte homeostasis in mice lacking the adhesion class G protein receptor CD97. Infect. Immun., 75 (3): 1144-53. [PMID:17158902]

30. Xiao J, Jiang H, Zhang R, Fan G, Zhang Y, Jiang D, Li H. (2012) Augmented cardiac hypertrophy in response to pressure overload in mice lacking ELTD1. PLoS ONE, 7 (5): e35779. [PMID:22606234]

31. Yagi H, Tokano H, Maeda M, Takabayashi T, Nagano T, Kiyama H, Fujieda S, Kitamura K, Sato M. (2007) Vlgr1 is required for proper stereocilia maturation of cochlear hair cells. Genes Cells, 12 (2): 235-50. [PMID:17295842]

32. Ying G, Wu S, Hou R, Huang W, Capecchi MR, Wu Q. (2009) The protocadherin gene Celsr3 is required for interneuron migration in the mouse forebrain. Mol. Cell. Biol., 29 (11): 3045-61. [PMID:19332558]

33. Zhou L, Bar I, Achouri Y, Campbell K, De Backer O, Hebert JM, Jones K, Kessaris N, de Rouvroit CL, O'Leary D, Richardson WD, Goffinet AM, Tissir F. (2008) Early forebrain wiring: genetic dissection using conditional Celsr3 mutant mice. Science, 320 (5878): 946-9. [PMID:18487195]

34. Zhou L, Qu Y, Tissir F, Goffinet AM. (2009) Role of the atypical cadherin Celsr3 during development of the internal capsule. Cereb. Cortex, 19 Suppl 1: i114-9. [PMID:19349379]

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