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    • Approximately mammalian genes encoding family

    2021-09-24

    Approximately 250 mammalian genes encoding family A (or rhodopsin-like) GPCRs have been cloned (Lee et al., 2001a). As yet, the total number of cloned GPCRs reported in the literature including the secretin and metabotropic glutamate-like families of GPCRs falls short of the projected 616 GPCR-encoding sequences observed from the complete human genome sequence (Venter et al., 2001). Despite the human genome sequencing efforts, much work is still required to identify and Z-Ligustilide synthesis the open reading frames (ORF) encoding the full complement of GPCR genes. Inserted into suitable expression vectors, these DNA sequences can be used to express the receptor in assays which will assist in ligand identification. For these reasons, we are continuing in our efforts to identify, catalog, compare and map the expression of GPCRs. We have recently reported the identification of the H4 histamine receptor (Nguyen et al., 2001), the cysteinyl leukotriene 2 receptor (Heise et al., 2000) and the oGPCR-encoding genes GPR26, GPR57, GPR58 (Lee et al., 2000), GPR61, GPR62, GPR63 and GPR77 (Lee et al., 2001b). We now report the cloning of ten additional oGPCR-encoding genes named GPR78, GPR80, GPR81, GPR82, GPR93, GPR94, GPR95, GPR101, GPR102 and GPR103 as well as a pseudogene ψGPR79. GPR78 and GPR81 most closely resemble the oGPCR genes GPR26 and HM74, respectively. GPR80, GPR93 and ψGPR79 shared highest identities with members of the purinoceptor family, while GPR82 encoded an oGPCR distantly related to the purinoceptor-like oGPCR genes GPR17 and GPR34. In addition, two novel genes GPR93 and GPR94 share significant identities with each other and with recently identified genes encoding the UDP-glucose (Chambers et al., 2000) and platelet ADP (P2Y12) receptors (Hollopeter et al., 2001, Zhang et al., 2001), which together comprise a clustered family of genes on chromosome 3. GPR101 shared distant identity with amine-binding GPCR genes, GPR102 shared identity with the PNR/GPR57/GPR58 amine receptor-like subfamily of GPCR genes and GPR103 shared identities with peptide-binding receptors, including the neuropeptide FF 2, neuropeptide Y2 and galanin GalR1 receptors. We have also detected mRNA transcripts in tissues for GPR78, GPR81, GPR94, GPR95, GPR101 and GPR103.
    Materials and methods
    Results
    Discussion Currently, ∼350 human GPCRs have been cloned, as listed on the GPCRDB (G protein-coupled receptor database, http://www.gpcr.org/7tm/), with ∼250 representing family A (or rhodopsin-like) GPCRs (Lee et al., 2001a). These receptors total approximately half the predicted 616 GPCR-encoding sequences contained in the human genome (Venter et al., 2001), although the veracity of this total number remains to be confirmed. The identification of genes encoding the novel GPCRs predicts the existence of novel signaling systems leading to the discovery of novel ligands, as demonstrated by recent reports describing the discovery of apelin (Tatemoto et al., 1998), prolactin-releasing peptide (Hinuma et al., 1998), orexin (Sakurai et al., 1998), melanin-concentrating hormone (Bachner et al., 1999, Chambers et al., 1999, Lembo et al., 1999, Saito et al., 1999, Shimomura et al., 1999) and urotensin II (Ames et al., 1999, Liu et al., 1999, Mori et al., 1999, Nothacker et al., 1999) receptor-ligand systems. As these GPCR genes (many of which were cloned in our laboratory) were used in methods that led to the discovery and identification of these ligands (Lee et al., 2001a), we are continuing to isolate and characterize these novel genes. We now report the discovery of ten novel oGPCRs and a pseudogene. GPR78 is a paralogue of GPR26, apparent from shared identities (56% in the TM regions), a lack of asparagine-linked extracellular glycosylation sites, a short amino terminus, and similar gene structure (Fig. 1). GPR78 and GPR26 encoded receptors with shared conserved cationic arginine and lysine residues in TM6 and TM7, respectively, two residues recognized to play a role in purinergic binding and found only in P2Y receptors (Erb et al., 1995, Jiang et al., 1997) (Fig. 1). However, we reported calcium mobilization assays of human astrocytoma 1321N1 cells and Xenopus laevis oocytes transfected with GPR26 were not responsive to nucleoside di- and tri-phosphates (Lee et al., 2000). We reported high levels of GPR26 expression in many brain regions (Lee et al., 2000), while GPR78 was detected only in the pituitary and placenta. However, the overall structural homology suggested that GPR78 and GPR26 may encode receptors that share a common endogenous ligand.