Article Figures & Data
Figures
- 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.
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.
- Fig. 3.
Chemical structures of nicotinic acid and related compounds (biological activities are in Table 1). CA, carboxylic acid. *, chiral center.
- Fig. 4.
Chemical structures of bicyclic pyrazole MK-0354, a highly selective partial agonist for the HCA2 receptor, and two later follow-up compounds.
- Fig. 5.
Novel acifran analogs. *, chiral center.
- Fig. 6.
Anthranilic acid derivatives and related compounds as high-affinity HCA2 receptor full agonists.
- Fig. 7.
Fumaric acid esters and aromatic acids as agonists for the HCA2 and HCA3 receptor.
- Fig. 8.
Pyridopyrimidinones as a new class of selective HCA2 receptor agonists.
- Fig. 9.
Allosteric agonist for the HCA2 receptor.
- Fig. 10.
Various classes of HCA3 receptor ligands.
- 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
- TABLE 1
Current HCA receptor nomenclature and receptor properties For further details, see IJzerman et al. (2010).
Properties HCA1 HCA2 HCA3 Previous names/aliases GPR81, GPR104, TA-GPCR, LACR, FKSG80 GPR109A, HM74a (human), PUMA-G (mouse), HM74b, NIACR1 GPR109B, HM74, NIACR2 Genomic location 12q24.31 (human), 5F (mouse) 12q24.31 (human), 5F (mouse) 12q24.31 (human) Amino acid length 346 (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 coupling Gi/Go Gi/Go Gi/Go Expression in human tissue Adipocytes Adipocytes, macrophages, neutrophils, epidermal Langerhans cells, keratinocytes, intestinal epithelial cells Adipocytes, neutrophils, macrophages, intestinal epithelial cells Cellular function Inhibition of lipolysis Inhibition of lipolysis, activation of immune cells Inhibition of lipolysis, activation of immune cells Phenotype of mice lacking receptor Reduced insulin-induced antilipolysis Lack of nicotinic acid effects on lipid plasma levels and of nicotinic acid-induced flushing Compound Rata Humanb GTPγS Binding Assay (EC50) [3H]Nicotinic Acid Binding Assay (Ki) GTPγS Binding Assay (EC50) [3H]Nicotinic Acid Binding Assay (Ki) Adipocytes Spleen Spleen HCA2 (Cloned) HCA2 (Cloned) Adipocytes μM Nicotinic acid 1.4 0.70 0.033 0.25 0.081 0.079 Acifran N.D. N.D. N.D. 2.1 1.1 0.83 Acipimox 10 6.6 0.31 6.0 5.1 4.3 3-Pyridine-acetic acid 16 17 0.40 5.5 0.54 0.55 Pyridazine-4-COOH 3.8 3.1 0.12 N.D. N.D. N.D. Pyrazine-2-COOH 26 22 0.76 N.D. N.D. N.D. 5-Me-nicotinic acid 30 30 0.72 8.7 4.12 3.68 5-Me-pyrazine-2-COOH 52 15 0.65 N.D. N.D. N.D. 6-Me-nicotinic acid 73 54 1.7 N.D. N.D. N.D. Nicotinic acid-1-oxide 80 74 3.2 N.D. N.D. N.D. 2-OH-nicotinic acid 132 N.D. N.D. N.D. N.D. N.D. Furan-3-COOH 142 N.D. N.D. N.D. N.D. N.D. Nicotinamide >1000 >1000 N.D. >1000 92 75 - 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
R1 R2 Ki EC50 RIA R1 Ki EC50 RIA μM % μM % Nicotinic acid 0.033 0.74 100 C6H5-CH2- 1.3 87 50 H H 0.59 22 85 C6H5-(CH2)2- 1.6 N.D. N.D. i-C3H7 H 0.68 22 68 C6H5-(CH2)3- 6.3 N.D. n.d. C3H7 H 0.14 5.1 70 3Cl-C6H4-CH2- 0.50 47 39 C4H9 H 0.072 2.3 81 4Cl-C6H4-CH2- 3.6 N.D. N.D. -C3H6- 0.16 7.0 56 4-CH3-C6H4-CH2- 20 N.D. N.D. -C4H8- 3.5 65 47 4-OCH3-C6H4-CH2- 66 N.D. N.D. N.D., not determined.
In this issue
International Union of Basic and Clinical Pharmacology. LXXXII: Nomenclature and Classification of Hydroxy-carboxylic Acid Receptors (GPR81, GPR109A, and GPR109B)
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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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