Class C Orphans: Introduction

GPRC5 Orphans

The first member of this group of orphan class C GPCRs was identified in 1998 by Cheng and Lotan as a novel retinoic acid-inducible gene called RAIG1.[3] The gene, mainly expressed in the lungs, encodes a protein with an heptahelical domain, and was found to share 25% sequence identity with Group-II mGlu receptors. However, this protein lacks the large extracellular domain of the other class C GPCRs. Following the sequencing of the human genome, additional RAIG1-like sequences were identified and cloned [1-2,7]. These were called GPRC5B, -C, and -D. All these receptors share high sequence homology with RAIG1, their expression is also increased after retinoic acid treatment, and they also lack the large extracellular domain. GPRC5B is expressed mostly in various brain areas, whereas GPRC5C and -D are found in peripheral tissues (stomach, pancreas, kidneys, and liver). No G-protein coupling of these receptors has been reported yet, despite the analysis of a number of chimeras generated with the CaS and mGlu receptors [1]. It is worth noting that the most conserved residues within the HD of classC GPCRs are not conserved in these retinoic acid-induced receptors. These include the two cysteines that link the top of TM3 and the second extracellular loop, the highly conserved Trp in TM6, and the conserved FNEAK motif at the bottom of TM6 (end of the third intracellular loop). One may wonder, therefore, whether these proteins are able to couple to G-proteins. These receptors also share a high sequence similarity (28% identity) with bride of sevenless (BOSS), although the latter has a large extracellular domain sharing no sequence similarity with the other family 3 GPCRs. BOSS was identified in Drosophila melanogaster as the ligand for the tyrosine kinase receptor sevenless, but no G-protein coupling was found for this protein yet.

Orphan nameK/O mouse Y/NPhenotype Y/NPhenotype descriptionReference
GPRC6AYesYesImpaired osteoblast function [6]
GPRC5AYesYesLung inflammation and tumourigenesis, elevated cytokine levels [5]
GPRC5BYesYesp97FE65 isoform-specific knockout mice exhibit learning and memory difficulties[4]


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1. Bräuner-Osborne H, Jensen AA, Sheppard PO, Brodin B, Krogsgaard-Larsen P, O'Hara P. (2001) Cloning and characterization of a human orphan family C G-protein coupled receptor GPRC5D. Biochim Biophys Acta, 1518: 237-248. [PMID:11311935]

2. Bräuner-Osborne H, Krogsgaard-Larsen P. (2000) Sequence and expression pattern of a novel human orphan G-protein-coupled receptor, GPRC5B, a family C receptor with a short amino-terminal domain. Genomics, 65 (2): 121-8. [PMID:10783259]

3. Cheng Y, Lotan R. (1998) Molecular cloning and characterization of a novel retinoic acid-inducible gene that encodes a putative G protein-coupled receptor. J Biol Chem, 273: 35008-35015. [PMID:9446598]

4. Cool BH, Chan GC, Lee L, Oshima J, Martin GM, Hu Q. (2010) A flanking gene problem leads to the discovery of a Gprc5b splice variant predominantly expressed in C57Bl/6J mouse brain and in maturing neurons. PLoS ONE, 5 (4): e10351. [PMID:20436672]

5. Deng J, Fujimoto J, Ye XF, Men TY, Van Pelt CS, Chen YL, Lin XF, Kadara H, Tao Q, Lotan D, Lotan R. (2010) Knockout of the tumor suppressor gene Gprc5a in mice leads to NF-kappaB activation in airway epithelium and promotes lung inflammation and tumorigenesis. Cancer Prev Res (Phila), 3 (4): 424-37. [PMID:20354164]

6. Pi M, Zhang L, Lei SF, Huang MZ, Zhu W, Zhang J, Shen H, Deng HW, Quarles LD. (2010) Impaired osteoblast function in GPRC6A null mice. J Bone Miner Res, 25 (5): 1092-102. [PMID:19874200]

7. Robbins MJ, Michalovich D, Hill J, Calver AR, Medhurst AD, Gloger I, Sims M, Middlemiss DN, Pangalos MN. (2000) Molecular cloning and characterization of two novel retinoic acid-inducible orphan G-protein-coupled receptors (GPRC5B and GPRC5C). Genomics, 67 (1): 8-18. [PMID:10945465]

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