RESUMO
In 2005, the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR) published a catalog of all of the human gene sequences known or predicted to encode G protein-coupled receptors (GPCRs), excluding sensory receptors. This review updates the list of orphan GPCRs and describes the criteria used by NC-IUPHAR to recommend the pairing of an orphan receptor with its cognate ligand(s). The following recommendations are made for new receptor names based on 11 pairings for class A GPCRs: hydroxycarboxylic acid receptors [HCA1 (GPR81) with lactate, HCA2 (GPR109A) with 3-hydroxybutyric acid, HCA3 (GPR109B) with 3-hydroxyoctanoic acid]; lysophosphatidic acid receptors [LPA4 (GPR23), LPA5 (GPR92), LPA6 (P2Y5)]; free fatty acid receptors [FFA4 (GPR120) with omega-3 fatty acids]; chemerin receptor (CMKLR1; ChemR23) with chemerin; CXCR7 (CMKOR1) with chemokines CXCL12 (SDF-1) and CXCL11 (ITAC); succinate receptor (SUCNR1) with succinate; and oxoglutarate receptor [OXGR1 with 2-oxoglutarate]. Pairings are highlighted for an additional 30 receptors in class A where further input is needed from the scientific community to validate these findings. Fifty-seven human class A receptors (excluding pseudogenes) are still considered orphans; information has been provided where there is a significant phenotype in genetically modified animals. In class B, six pairings have been reported by a single publication, with 28 (excluding pseudogenes) still classified as orphans. Seven orphan receptors remain in class C, with one pairing described by a single paper. The objective is to stimulate research into confirming pairings of orphan receptors where there is currently limited information and to identify cognate ligands for the remaining GPCRs. Further information can be found on the IUPHAR Database website (http://www.iuphar-db.org).
Assuntos
Ligantes , Receptores Acoplados a Proteínas G/metabolismo , Animais , Genótipo , Humanos , Fenótipo , Pseudogenes , Receptores Acoplados a Proteínas G/classificação , Receptores Acoplados a Proteínas G/genéticaRESUMO
A gene encoding a novel class a G-protein-coupled receptor was discovered in 1993 by homology cloning and was called APJ. It was designated an "orphan" receptor until 1998, when its endogenous ligand was identified and named apelin (for APJ endogenous ligand). Since this pairing, both apelin and its receptor have been found to have a widespread distribution in both the central nervous system and the periphery. A number of physiological and pathophysiological roles for the receptor have emerged, including regulation of cardiovascular function, fluid homeostasis, and the adipoinsular axis. This review outlines the official International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification nomenclature, designating the receptor protein as the apelin receptor, together with current knowledge of its pharmacology, distribution, and functions.
Assuntos
Receptores Acoplados a Proteínas G/classificação , Adipocinas , Animais , Apelina , Receptores de Apelina , Proteínas de Transporte/química , Proteínas de Transporte/classificação , Proteínas de Transporte/fisiologia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Ratos , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/fisiologia , Terminologia como AssuntoRESUMO
Since its start, the Mammalian Gene Collection (MGC) has sought to provide at least one full-protein-coding sequence cDNA clone for every human and mouse gene with a RefSeq transcript, and at least 6200 rat genes. The MGC cloning effort initially relied on random expressed sequence tag screening of cDNA libraries. Here, we summarize our recent progress using directed RT-PCR cloning and DNA synthesis. The MGC now contains clones with the entire protein-coding sequence for 92% of human and 89% of mouse genes with curated RefSeq (NM-accession) transcripts, and for 97% of human and 96% of mouse genes with curated RefSeq transcripts that have one or more PubMed publications, in addition to clones for more than 6300 rat genes. These high-quality MGC clones and their sequences are accessible without restriction to researchers worldwide.
Assuntos
Clonagem Molecular/métodos , Biologia Computacional/métodos , DNA Complementar/genética , Biblioteca Gênica , Genes/genética , Mamíferos/genética , Animais , DNA/biossíntese , Humanos , Camundongos , National Institutes of Health (U.S.) , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estados UnidosRESUMO
Trace amines such as p-tyramine and beta-phenylethylamine are found endogenously as well as in the diet. Concomitant ingestion of these foodstuffs with monoamine oxidase inhibitors may result in the hypertensive crisis known as the "beer, wine, and cheese effect" attributed to their sympathomimetic action. Trace amines have been shown to act on one of a novel group of mammalian seven transmembrane spanning G protein-coupled receptors belonging to the rhodopsin superfamily, cloned in 2001. This receptor encoded by the human TAAR1 gene is also present in rat and mouse genomes (Taar1) and has been shown to be activated by endogenous trace amine ligands, including p-tyramine and beta-phenylethylamine. A number of drugs, most notably amphetamine and its derivatives, act as agonists at this receptor. This review proposes an official nomenclature designating TAAR1 as the trace amine 1 receptor following the convention of naming receptors after the endogenous agonist, abbreviated to TA(1) where necessary. It goes on to discuss briefly the significance of the receptor, agents acting upon it, its distribution, and currently hypothesized physiological and pathophysiological roles. In humans, a further five genes are thought to encode functional receptors (TAAR2, TAAR5, TAAR6, TAAR8, and TAAR9). TAAR3 seems to be a pseudogene in some individuals but not others. TAAR4 is a pseudogene in humans, but occurs with TAAR3 as a functional gene in rodents. Nine further genes are present in rats and mice. The endogenous ligands are not firmly established but some may respond to odorants consistent with their expression in olfactory epithelium.
Assuntos
Receptores Acoplados a Proteínas G/classificação , Terminologia como Assunto , Animais , Humanos , Agências Internacionais , LigantesRESUMO
The IUPHAR database (IUPHAR-DB) integrates peer-reviewed pharmacological, chemical, genetic, functional and anatomical information on the 354 nonsensory G protein-coupled receptors (GPCRs), 71 ligand-gated ion channel subunits and 141 voltage-gated-like ion channel subunits encoded by the human, rat and mouse genomes. These genes represent the targets of approximately one-third of currently approved drugs and are a major focus of drug discovery and development programs in the pharmaceutical industry. IUPHAR-DB provides a comprehensive description of the genes and their functions, with information on protein structure and interactions, ligands, expression patterns, signaling mechanisms, functional assays and biologically important receptor variants (e.g. single nucleotide polymorphisms and splice variants). In addition, the phenotypes resulting from altered gene expression (e.g. in genetically altered animals or in human genetic disorders) are described. The content of the database is peer reviewed by members of the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR); the data are provided through manual curation of the primary literature by a network of over 60 subcommittees of NC-IUPHAR. Links to other bioinformatics resources, such as NCBI, Uniprot, HGNC and the rat and mouse genome databases are provided. IUPHAR-DB is freely available at http://www.iuphar-db.org.
Assuntos
Bases de Dados de Proteínas , Canais Iônicos/genética , Canais Iônicos/fisiologia , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/fisiologia , Animais , Descoberta de Drogas , Humanos , Canais Iônicos/química , Ligantes , Camundongos , Subunidades Proteicas/química , Subunidades Proteicas/genética , Subunidades Proteicas/fisiologia , Ratos , Receptores Acoplados a Proteínas G/químicaRESUMO
Sequence annotation is essential for genomics-based research. Investigators of a specific genomic region who have developed abundant local discoveries such as genes and genetic markers, or have collected annotations from multiple resources, can be overwhelmed by the difficulty in creating local annotation and the complexity of integrating all the annotations. Presenting such integrated data in a form suitable for data mining and high-throughput experimental design is even more daunting. DNannotator, a web application, was designed to perform batch annotation on a sizeable genomic region. It takes annotation source data, such as SNPs, genes, primers, and so on, prepared by the end-user and/or a specified target of genomic DNA, and performs de novo annotation. DNannotator can also robustly migrate existing annotations in GenBank format from one sequence to another. Annotation results are provided in GenBank format and in tab-delimited text, which can be imported and managed in a database or spreadsheet and combined with existing annotation as desired. Graphic viewers, such as Genome Browser or Artemis, can display the annotation results. Reference data (reports on the process) facilitating the user's evaluation of annotation quality are optionally provided. DNannotator can be accessed at http://sky.bsd.uchicago.edu/DNannotator.htm.
Assuntos
Genômica/métodos , Análise de Sequência de DNA/métodos , Software , Cromossomos Humanos Par 13 , Primers do DNA , Genoma Humano , Humanos , Internet , Polimorfismo de Nucleotídeo Único , Sitios de Sequências Rotuladas , Interface Usuário-ComputadorRESUMO
Antibodies designed to recognize a 74 amino acid sequence of the N- or C-terminal domain of the rat CB1 cannabinoid receptor detected a 58 kDa protein in immunoblots of brain and various cells known to express the CB1 cannabinoid receptor. A human B-lymphoblastoid cell line and macrophage-like cells from neonatal rat brain were also positive for CB1 receptor-like immunoreactivity. Immunocytochemical analysis performed with isolated Fab fragments showed surface staining in NG108-15 cells and brain macrophage like cells which also express MHC class II antigens. The data suggest a plausible role for CB1 receptors in the immune function of brain.
Assuntos
Encéfalo/imunologia , Microglia/química , Receptores de Droga/genética , Receptores de Droga/imunologia , Animais , Animais Recém-Nascidos , Especificidade de Anticorpos , Encéfalo/citologia , Química Encefálica/imunologia , Células CHO , Canabinoides/genética , Canabinoides/imunologia , Cricetinae , Feminino , Proteínas de Ligação ao GTP/imunologia , Expressão Gênica , Macrófagos/química , Macrófagos/imunologia , Microglia/imunologia , Coelhos , Ratos , Receptores de Canabinoides , Receptores de Droga/análise , Proteínas Recombinantes de Fusão/imunologia , Schistosoma japonicumRESUMO
NC-IUPHAR (International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification) and its subcommittees provide authoritative reports on the nomenclature and pharmacology of G protein-coupled receptors (GPCRs) that summarize their structure, pharmacology, and roles in physiology and pathology. These reports are published in Pharmacological Reviews (http://www.iuphar.org/nciuphar_arti.html) and through the International Union of Pharmacology (IUPHAR) Receptor Database web site (http://www.iuphar-db.org/iuphar-rd). The essentially complete sequencing of the human genome has allowed the cataloging of all of the human gene sequences potentially encoding GPCRs. The IUPHAR Receptor List (http://www.iuphar-db.org/iuphar-rd/list/index.htm) presents this catalog giving IUPHAR-approved nomenclature (where available), known ligands, and gene names for all of these potential receptors (excluding sensory receptors and pseudogenes) together with links to curated sequence, descriptive information, and additional links in the Entrez Gene database (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene). This list is a major new initiative of NC-IUPHAR that, through continuing curation, defines the target of our ongoing receptor classification and invites further input from the scientific community.
Assuntos
Receptores Acoplados a Proteínas G/classificação , Terminologia como Assunto , Animais , Humanos , Agências Internacionais , Receptores Acoplados a Proteínas G/genéticaRESUMO
Genome-wide scans in bipolar disorder and a meta analysis on published data have provided evidence for linkage to chromosome 13q, although the reported peaks from various studies have not converged in a narrow region. Recently, single nucleotide polymorphisms (SNPs) at the G72/G30 locus have been shown to be associated with bipolar disorder suggesting its potential role in increasing disease risk. The proposed linkage region on 13q extends over a wide span, and could provide a clue to the existence of other susceptibility variants. In the present study, SNPs in the LOC93081-KDELC1-BIVM, a region proximal to G72, were interrogated in two bipolar family series. KDELC1 has a predicted filamin domain and BIVM contains an immunoglobulin-like motif. The small pedigree series yielded a nominally significant global P-value due to under-transmission of a rare haplotype but this finding was not supported by results from the larger series and in the case-control study that compared 278 cases and 277 controls.
Assuntos
Transtorno Bipolar/genética , Cromossomos Humanos Par 13/genética , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único , Alelos , Estudos de Casos e Controles , Proteínas Contráteis/genética , DNA/química , DNA/genética , Análise Mutacional de DNA , Saúde da Família , Feminino , Filaminas , Frequência do Gene , Genótipo , Haplótipos , Humanos , Imunoglobulinas/genética , Masculino , Proteínas dos Microfilamentos/genética , Repetições de Microssatélites , LinhagemRESUMO
Ghrelin is a 28-amino acid peptide originally isolated from rat stomach and is cleaved from a 117-amino acid precursor. The sequence of the mature peptide from rats and mice differs by two amino acids from that of human ghrelin. Alternative splicing of the ghrelin gene transcript can result in the translation of a second biologically active peptide, des-Gln14-ghrelin. Both peptides have a unique post-translational modification, octanoylation of Ser3, which is essential for the binding to receptors in hypothalamus and pituitary and stimulating the release of growth hormone from the pituitary. The growth hormone secretagogue receptor (GHS-R1a, Swiss-Prot code Q92847, LocusLink ID 2693), a rhodopsin-like seven transmembrane spanning G protein-coupled receptors belonging to Family A, was cloned in 1996 from the pituitary and hypothalamus and shown to be the target of growth hormone secretagogues (GHS), a class of synthetic peptide and nonpeptide compounds causing growth hormone release from the anterior pituitary. In 1999, ghrelin was identified as the endogenous cognate ligand for this receptor. The purpose of this review is to propose an official International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR) nomenclature designating GHS-R1a as the ghrelin receptor to follow the convention of naming receptors after the endogenous agonist, abbreviated where necessary to GRLN.
Assuntos
Receptores Acoplados a Proteínas G/fisiologia , Animais , Humanos , Dados de Sequência Molecular , Receptores Acoplados a Proteínas G/classificação , Receptores Acoplados a Proteínas G/efeitos dos fármacos , Receptores Acoplados a Proteínas G/genética , Receptores de Grelina , Relação Estrutura-Atividade , Terminologia como Assunto , Distribuição TecidualRESUMO
Linkage evidence suggests that chromosome 13 (13q32-33) contains susceptibility genes for both bipolar disorder and schizophrenia. Recently, genes called "G72" and "G30" were identified, and polymorphisms of these overlapping genes were reported to be associated with schizophrenia. We studied two series of pedigrees with bipolar disorder: the Clinical Neurogenetics (CNG) pedigrees (in which linkage to illness had been previously reported at 13q32-33), with 83 samples from 22 multiplex families, and the National Institute of Mental Health (NIMH) Genetics Initiative pedigrees, with 474 samples from 152 families. Sixteen single-nucleotide polymorphisms (SNPs) were genotyped at and around the G72/G30 locus, which covered a 157-kb region encompassing the entire complementary DNA sequences of G72 and G30. We performed transmission/disequilibrium testing (TDT) and haplotype analysis, since a linkage-disequilibrium block was present at this gene locus. In the CNG and NIMH data sets, the results of global TDT of the entire haplotype set were significant and consistent (P=.0004 and P=.008, respectively). In the CNG series, the associated genotypes divided the families into those with linkage and those without linkage (partitioned by the linkage evidence). Analysis of the decay of haplotype sharing gave a location estimate that included G72/G30 in its 95% confidence interval. Although statistically significant association was not detected for individual SNPs in the NIMH data set, the same haplotype was consistently overtransmitted in both series. These data suggest that a susceptibility variant for bipolar illness exists in the vicinity of the G72/G30 genes. Taken together with the earlier report, this is the first demonstration of a novel gene(s), discovered through a positional approach, independently associated with both bipolar illness and schizophrenia.
Assuntos
Transtorno Bipolar/genética , Proteínas de Transporte/genética , Cromossomos Humanos Par 13/genética , Genes , Polimorfismo de Nucleotídeo Único , Processamento Alternativo , DNA Complementar/genética , Frequência do Gene , Ligação Genética , Predisposição Genética para Doença , Haplótipos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Funções Verossimilhança , Desequilíbrio de Ligação , Dados de Sequência Molecular , Linhagem , Análise de Sequência de DNARESUMO
We have recently mapped a locus for hereditary prostate cancer (termed HPCX) to the long arm of the X chromosome (Xq25-q27) through a genome-wide linkage study. Here we report the construction of an approximately 9-Mb sequence-ready bacterial clone contig map of Xq26.3-q27.3. The contig was constructed by screening BAC/PAC libraries with markers spaced at approximately 85-kb intervals. We identified overlapping clones by end-sequencing framework clones to generate 407 new sequence-tagged sites, followed by PCR verification of overlaps. Contig assembly was based on clone restriction fingerprinting and the landmark information. We identified a minimal overlap contig for genomic sequencing, which has yielded 7.7 Mb of finished sequence and 1.5 Mb of draft sequence. The transcriptional mapping effort localized 57 known and predicted genes by database searching, STS content mapping, and sequencing, followed by sequence annotation. These transcriptional units represent candidate genes for HPCX and multiple other hereditary diseases at Xq26.3-q27.3.
Assuntos
Mapeamento Cromossômico , Neoplasias da Próstata/genética , Cromossomo X/genética , Cromossomos Artificiais Bacterianos/genética , Cromossomos Artificiais de Bacteriófago P1/genética , Humanos , Masculino , Dados de Sequência Molecular , Neoplasias da Próstata/etiologia , RNA Mensageiro/genética , Análise de Sequência de DNA , Cromossomo X/ultraestruturaRESUMO
The National Institutes of Health's Mammalian Gene Collection (MGC) project was designed to generate and sequence a publicly accessible cDNA resource containing a complete open reading frame (ORF) for every human and mouse gene. The project initially used a random strategy to select clones from a large number of cDNA libraries from diverse tissues. Candidate clones were chosen based on 5'-EST sequences, and then fully sequenced to high accuracy and analyzed by algorithms developed for this project. Currently, more than 11,000 human and 10,000 mouse genes are represented in MGC by at least one clone with a full ORF. The random selection approach is now reaching a saturation point, and a transition to protocols targeted at the missing transcripts is now required to complete the mouse and human collections. Comparison of the sequence of the MGC clones to reference genome sequences reveals that most cDNA clones are of very high sequence quality, although it is likely that some cDNAs may carry missense variants as a consequence of experimental artifact, such as PCR, cloning, or reverse transcriptase errors. Recently, a rat cDNA component was added to the project, and ongoing frog (Xenopus) and zebrafish (Danio) cDNA projects were expanded to take advantage of the high-throughput MGC pipeline.