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Research ArticleIUPHAR Nomenclature Report

International Union of Basic and Clinical Pharmacology. LXXXII: Nomenclature and Classification of Hydroxy-carboxylic Acid Receptors (GPR81, GPR109A, and GPR109B)

Stefan Offermanns, Steven L. Colletti, Timothy W. Lovenberg, Graeme Semple, Alan Wise and Adriaan P. IJzerman
Pharmacological Reviews June 2011, 63 (2) 269-290; DOI: https://doi.org/10.1124/pr.110.003301
Stefan Offermanns
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Steven L. Colletti
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Timothy W. Lovenberg
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Graeme Semple
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Alan Wise
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Adriaan P. IJzerman
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  • Fig. 1.
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    Fig. 1.

    Amino acid sequence alignment of HCA1, HCA2, and HCA3 as well as of the related receptors GPR31 and OXER1 (TG1019, GPR170) based on the Clustal V method. Transmembrane regions are indicated by gray boxes. Two short sequences in the N-terminal part of OXER1 (residues 6–39 and 52–80) have been omitted to facilitate the alignment (gaps are indicated by asterisks). Positions with identical amino acids in HCA1, HCA2, and HCA3 are marked by one asterisk (*), positions with identical residues in all five receptors are indicated by two asterisks (**).

  • Fig. 2.
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    Fig. 2.

    A, phylogenetic tree and percentage amino acid sequence identity of the human hydroxy-carboxylic acid receptors HCA1, HCA2, and HCA3 as well as of the most related human receptors GPR31 and the 5-oxo-ETE receptor OXER1 (GPR170, TG1019). Data are based on an alignment by the Clustal W method. B, schematic representation of the genomic organization of the genes encoding hydroxy-carboxylic acid receptors.

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    Fig. 3.

    Chemical structures of nicotinic acid and related compounds (biological activities are in Table 1). CA, carboxylic acid. *, chiral center.

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    Fig. 4.

    Chemical structures of bicyclic pyrazole MK-0354, a highly selective partial agonist for the HCA2 receptor, and two later follow-up compounds.

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    Fig. 5.

    Novel acifran analogs. *, chiral center.

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    Fig. 6.

    Anthranilic acid derivatives and related compounds as high-affinity HCA2 receptor full agonists.

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    Fig. 7.

    Fumaric acid esters and aromatic acids as agonists for the HCA2 and HCA3 receptor.

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    Fig. 8.

    Pyridopyrimidinones as a new class of selective HCA2 receptor agonists.

  • Fig. 9.
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    Fig. 9.

    Allosteric agonist for the HCA2 receptor.

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    Fig. 10.

    Various classes of HCA3 receptor ligands.

  • Fig. 11.
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    Fig. 11.

    Functions of the recently deorphanized receptors HCA1, HCA2, and HCA3. The lactate receptor HCA1 mediates the short-term anabolic effects of insulin on adipocytes and thereby helps to store energy after feeding (A). In contrast, HCA2 and HCA3 receptors are involved in the long-term regulation of lipolytic activity, being receptors for the ketone body 3-hydroxy-butyrate (HCA2) and the β-oxidation intermediate 3-hydroxy-octanoate (HCA3). In situations of increased β-oxidation rates (e.g., during starvation), 3-hydroxy-butyrate and 3-hydroxy-octanoate plasma levels are increased and result in the inhibitory regulation of lipolysis via HCA2 and HCA3 receptors, respectively, in the form of a negative feedback loop (B). Thereby, HCA2 and HCA3 receptors help preserve energy stores during starvation. AC, adenylyl cyclase; TG, triglycerides; HSL, homon-sensitive lipase; ATGL, adipocyte triglyceride lipase; FFA, free fatty acids; PKA, cAMP-regulated protein kinase.

Tables

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    TABLE 1

    Current HCA receptor nomenclature and receptor properties For further details, see IJzerman et al. (2010).

    PropertiesHCA1HCA2HCA3
    Previous names/aliasesGPR81, GPR104, TA-GPCR, LACR, FKSG80GPR109A, HM74a (human), PUMA-G (mouse), HM74b, NIACR1GPR109B, HM74, NIACR2
    Genomic location12q24.31 (human), 5F (mouse)12q24.31 (human), 5F (mouse)12q24.31 (human)
    Amino acid length346 (human), 343 (mouse)363 (human), 360 (mouse)387 (human)
    Naturally occurring specific agonists (pEC50)2-OH-propanoate (2.5–2.8)3-OH-butyrate (3.1), nicotinic acid (6.6–7.2)3-OH-octanoate (5.1), 2-OH-octanoate (5.4), D-phenylalanine (5.0), D-tryptophan (5.4)
    Specific synthetic agonists (pEC50)acipimox (5.2–5.6)1-Isopropylbenzo-triazole-5-carboxylic acid (6.4), 5-methyl-5-(5-methyl-thio-phen-3-yl)-4-oxo-4,5-dihydro-furan-2-carboxylic acid (6.7)
    G-protein couplingGi/GoGi/GoGi/Go
    Expression in human tissueAdipocytesAdipocytes, macrophages, neutrophils, epidermal Langerhans cells, keratinocytes, intestinal epithelial cellsAdipocytes, neutrophils, macrophages, intestinal epithelial cells
    Cellular functionInhibition of lipolysisInhibition of lipolysis, activation of immune cellsInhibition of lipolysis, activation of immune cells
    Phenotype of mice lacking receptorReduced insulin-induced antilipolysisLack of nicotinic acid effects on lipid plasma levels and of nicotinic acid-induced flushing
    • View popup
    TABLE 2

    EC50 and Ki values of nicotinic acid and related compounds

    CompoundRataHumanb
    GTPγS Binding Assay (EC50)[3H]Nicotinic Acid Binding Assay (Ki)GTPγS Binding Assay (EC50)[3H]Nicotinic Acid Binding Assay (Ki)
    AdipocytesSpleenSpleenHCA2 (Cloned)HCA2 (Cloned)Adipocytes
    μM
    Nicotinic acid1.40.700.0330.250.0810.079
    AcifranN.D.N.D.N.D.2.11.10.83
    Acipimox106.60.316.05.14.3
    3-Pyridine-acetic acid16170.405.50.540.55
    Pyridazine-4-COOH3.83.10.12N.D.N.D.N.D.
    Pyrazine-2-COOH26220.76N.D.N.D.N.D.
    5-Me-nicotinic acid30300.728.74.123.68
    5-Me-pyrazine-2-COOH52150.65N.D.N.D.N.D.
    6-Me-nicotinic acid73541.7N.D.N.D.N.D.
    Nicotinic acid-1-oxide80743.2N.D.N.D.N.D.
    2-OH-nicotinic acid132N.D.N.D.N.D.N.D.N.D.
    Furan-3-COOH142N.D.N.D.N.D.N.D.N.D.
    Nicotinamide>1000>1000N.D.>10009275
    • N.D., not determined.

    • ↵a Lorenzen et al. (2001).

    • ↵b Wise et al. (2003).

    • View popup
    TABLE 3

    Affinities (Ki values in radioligand displacement study), potencies (EC50 values in [35S]GTPγS binding assay), and relative intrinsic activities (RIA; [35S]GTPγS binding assay) of pyrazole-derived partial agonists for the rat nicotinic acid receptor

    Embedded ImageEmbedded Image
    R1R2KiEC50RIAR1KiEC50RIA
    μM%μM%
    Nicotinic acid0.0330.74100C6H5-CH2-1.38750
    HH0.592285C6H5-(CH2)2-1.6N.D.N.D.
    i-C3H7H0.682268C6H5-(CH2)3-6.3N.D.n.d.
    C3H7H0.145.1703Cl-C6H4-CH2-0.504739
    C4H9H0.0722.3814Cl-C6H4-CH2-3.6N.D.N.D.
    -C3H6-0.167.0564-CH3-C6H4-CH2-20N.D.N.D.
    -C4H8-3.565474-OCH3-C6H4-CH2-66N.D.N.D.
    • N.D., not determined.

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Pharmacological Reviews: 63 (2)
Pharmacological Reviews
Vol. 63, Issue 2
1 Jun 2011
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Research ArticleIUPHAR Nomenclature Report

International Union of Basic and Clinical Pharmacology. LXXXII: Nomenclature and Classification of Hydroxy-carboxylic Acid Receptors (GPR81, GPR109A, and GPR109B)

Stefan Offermanns, Steven L. Colletti, Timothy W. Lovenberg, Graeme Semple, Alan Wise and Adriaan P. IJzerman
Pharmacological Reviews June 1, 2011, 63 (2) 269-290; DOI: https://doi.org/10.1124/pr.110.003301

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Research ArticleIUPHAR Nomenclature Report

International Union of Basic and Clinical Pharmacology. LXXXII: Nomenclature and Classification of Hydroxy-carboxylic Acid Receptors (GPR81, GPR109A, and GPR109B)

Stefan Offermanns, Steven L. Colletti, Timothy W. Lovenberg, Graeme Semple, Alan Wise and Adriaan P. IJzerman
Pharmacological Reviews June 1, 2011, 63 (2) 269-290; DOI: https://doi.org/10.1124/pr.110.003301
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  • Article
    • Abstract
    • I. Introduction
    • II. Molecular Basis for Receptor Nomenclature
    • III. Receptor Mutagenesis and Modeling Studies
    • IV. Gene Structure, Expression, and Regulation
    • V. Receptor Classification with Pharmacological Tools
    • VI. Receptor Signaling and Regulation
    • VII. Biological Roles
    • VIII. Therapeutic Potential of Hydroxy-carboxylic Acid Receptor Ligands
    • IX. Conclusion
    • Acknowledgments
    • Authorship Contributions
    • Footnotes
    • References
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