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    • GPR GPR GPR GPR and

    2021-12-07

    GPR80, GPR81, GPR82, GPR93 and ψGPR79 all shared identities to P2Y GPCRs or P2Y-like oGPCRs. Previously, at least three different nucleotide receptor phenotypes have been observed in mammalian tissue, including GPCRs activated by PAI-039 nucleotides (e.g. P2Y1 and P2Y11), uridine nucleotides (e.g. P2Y6) and by both adenine and uridine (e.g. P2Y2 and P2Y4) (King et al., 1998). ψGPR79 shared closest identity with P2Y and P2Y, even though it does not encode a functional GPCR. GPR80 was observed to share highest identity with P2Y1, while GPR81, GPR82 and GPR93 shared identities with the P2Y-like oGPCR genes HM74, GPR34 and P2Y, respectively. Some of these oGPCR genes encode aa residues conserved amongst the P2Y receptors and shown to be involved in purinergic ligand binding (Erb et al., 1995, Hoffmann et al., 1999, Jiang et al., 1997) (Fig. 1). While expression was not observed for GPR80, GPR82 and GPR93 in various CNS regions, GPR81 was observed to have an mRNA transcript in the pituitary, suggesting a role in neuroendocrine regulation. The identities of GPR94 and GPR95 with the genes encoding the UDP-glucose and P2Y12 receptors (>50% in the TM regions) indicate a novel subfamily of purinergic-like receptors. Previously, the UDP-glucose receptor was reported to have a distant sequence homology with the P2Y receptors, with an observed widespread tissue distribution in human brain and such peripheral tissues as placenta, adipose tissue, spleen, intestine, stomach, skeletal muscle, lung and heart (Chambers et al., 2000). The identification of the platelet ADP (P2Y12) receptor resulted from cDNA isolated from rat platelets and human hypothalamus (Zhang et al., 2001, Hollopeter et al., 2001). An alignment of these receptors with the GPCRs encoded by GPR94 and GPR95 revealed several residues conserved in P2Y purinoceptors (see above) also conserved throughout this novel purinoceptor-like subfamily (Fig. 1). Northern analysis of GPR94 mRNA revealed expression in various regions of the brain, suggesting a neuromodulatory role. In contrast, GPR95 mRNA was detected in peripheral tissue (i.e. human prostate and rat stomach). The receptor encoded by GPR101 appeared to be a distant relative of the biogenic amine superfamily of GPCRs, with TM identities of ∼30% with the adrenergic and serotonin receptors, as well as the muscarinic and dopamine receptors (data not shown). GPR101 mRNA transcripts were observed in brain tissue, suggesting the presence of an endogenous amine neurotransmitter ligand, perhaps novel in identity. The receptor encoded by GPR102 shared significant TM identities with an amine binding receptor-like GPCR family (including PNR, GPR57 and GPR58) suggesting they may also share a common endogenous ligand. The receptor encoded by GPR103 shared highest identities with several neuropeptide receptors. The significant levels of GPR103 expression in the brain, particularly in the thalamus and hypothalamus, suggest an endogenous peptide ligand, perhaps involved in physiological functions such as pain modulation and neuroendocrine regulation. Interestingly, some of these novel oGPCR genes appear to be clustered on various human chromosomes. The GPR81 gene was localized to chromosome 12q, proximal to the closely related oGPCR gene, HM74. The GPR82 gene was retrieved together with the GPR34 gene in a human BAC clone localized on chromosome 1. Another search of the HTGS database revealed GPR94, GPR95 and P2Y localized within the same BAC clone on chromosome 3. This cluster of genes also includes the UDP-glucose receptor gene, which together with the more distant P2Y1 receptor gene further localizes this cluster to chromosome 3q24-25 (interval D3S1279-1280) (Hollopeter et al., 2001). We have previously reported clusters of homologous GPCRs genes, including the GPR40 through GPR43 gene cluster (Sawzdargo et al., 1997) as well as the 5-HT4-like pseudogene, ψGPR57, GPR58 and PNR gene cluster (Lee et al., 2000). Given the significant sequence similarity of GPR102 with PNR, GPR57 and GPR58 and its localization on chromosome 6, GPR102 may be another paralogue member of this gene cluster.