Learn and talk about GHB receptor, G protein coupled receptors, Genes on chromosome 8, Receptors

G protein-coupled receptor 172A
Identifiers
Symbol	GPR172A
Entrez	79581
HUGO	30224
OMIM	607882
RefSeq	NM_024531
UniProt	Q9HAB3
Other data
Locus	Chr. 8 q24.3

Gamma-hydroxybutyrate receptor or GHB receptor (GHBR or GHBr), originally identified as GPR172A, is a G protein-coupled receptor that binds gamma-Hydroxybutyric acid (GHB).

1 History
2 Function
3 Selective Ligands
- 3.1 Agonists
- 3.2 Antagonists
4 References

History [edit]

The existence of a specific GHB receptor was predicted by observing the action of GHB and related compounds that primarily act on GABA_B receptors, but also exhibit a range of effects which were found not to be produced by GABA_B activity, and so were suspected of being produced by a novel and at the time unidentified receptor target. Following the discovery of the "orphan" G-protein coupled receptor GPR172A, it was subsequently found to be the GHB receptor whose existence had been previously predicted.^[1] The rat GHB receptor was first cloned and characterised in 2003^[2] followed by the human receptor in 2007.^[3]

Function [edit]

The function of the GHB receptor appears to be quite different from that of the GABA_B receptor. It shares no sequence homology with GABA_B, and administration of mixed GHBR/GABA_B agonists along with a selective GABA_B antagonist or selective agonists for the GHB receptor which are not agonists at GABA_B, do not produce a sedative effect, instead causing a stimulant effect followed by convulsions at higher doses, thought to be mediated through increased Na⁺/K⁺ current and increased release of dopamine and glutamate.^[4]^[5]^[6]^[7]^[8]^[9]

Selective Ligands [edit]

(R)-4-[4′-(2-iodobenzyloxy)phenyl]-GHB^[10]

Agonists [edit]

gamma-Hydroxybutyric acid
trans-hydroxycrotonic acid
UMB66
UMB68
UMB72
UMB86^[11]
(R)-3-Hydroxycyclopent-1-enecarboxylic acid
NCS-356: 4-(4-Chlorophenyl)-4-hydroxy-but-2-enoic acid, CAS# 430440-66-7
NCS-435: 4-(p-Methoxybenzyl)-GHB
HOCPCA: 3-hydroxycyclopent-1-enecarboxylic acid
4-(p-Chlorobenzyl)-GHB

Antagonists [edit]

NCS-382

References [edit]

^ Snead OC (November 2000). "Evidence for a G protein-coupled gamma-hydroxybutyric acid receptor". J. Neurochem. 75 (5): 1986–96. doi:10.1046/j.1471-4159.2000.0751986.x. PMID 11032888.
^ Andriamampandry C, Taleb O, Viry S, et al. (September 2003). "Cloning and characterization of a rat brain receptor that binds the endogenous neuromodulator gamma-hydroxybutyrate (GHB)". FASEB J. 17 (12): 1691–3. doi:10.1096/fj.02-0846fje. PMID 12958178.
^ Andriamampandry C, Taleb O, Kemmel V, Humbert JP, Aunis D, Maitre M (March 2007). "Cloning and functional characterization of a gamma-hydroxybutyrate receptor identified in the human brain". FASEB J. 21 (3): 885–95. doi:10.1096/fj.06-6509com. PMID 17197387.
^ Cash, C; Gobaille, S; Kemmel, V; Andriamampandry, C; Maitre, M (1999). "γ-hydroxybutyrate receptor function studied by the modulation of nitric oxide synthase activity in rat frontal cortex punches". Biochemical Pharmacology 58 (11): 1815–9. doi:10.1016/S0006-2952(99)00265-8. PMID 10571257.
^ Maitre M, Humbert JP, Kemmel V, Aunis D, Andriamampandry C (March 2005). "[A mechanism for gamma-hydroxybutyrate (GHB) as a drug and a substance of abuse]" [A mechanism for gamma-hydroxybutyrate (GHB) as a drug and a substance of abuse]. Med Sci (Paris) (in French) 21 (3): 284–9. doi:10.1051/medsci/2005213284. PMID 15745703.
^ Castelli MP, Ferraro L, Mocci I, et al. (November 2003). "Selective gamma-hydroxybutyric acid receptor ligands increase extracellular glutamate in the hippocampus, but fail to activate G protein and to produce the sedative/hypnotic effect of gamma-hydroxybutyric acid". J. Neurochem. 87 (3): 722–32. doi:10.1046/j.1471-4159.2003.02037.x. PMID 14535954.
^ Castelli MP (November 2008). "Multi-faceted aspects of gamma-hydroxybutyric Acid: a neurotransmitter, therapeutic agent and drug of abuse". Mini Rev Med Chem 8 (12): 1188–202. doi:10.2174/138955708786141025. PMID 18855733.
^ Crunelli V, Emri Z, Leresche N (February 2006). "Unravelling the brain targets of γ-hydroxybutyric acid". Curr Opin Pharmacol 6 (1): 44–52. doi:10.1016/j.coph.2005.10.001. PMC 2174623. PMID 16368267.
^ Carter LP, Koek W, France CP (October 2008). "Behavioral Analyses of GHB: Receptor Mechanisms". Pharmacol. Ther. 121 (1): 100–14. doi:10.1016/j.pharmthera.2008.10.003. PMC 2631377. PMID 19010351.
^ Høg S, Wellendorph P, Nielsen B, et al. (2008). "Novel High-Affinity and Selective Biaromatic 4-Substituted gamma-Hydroxybutyric Acid (GHB) Analogues as GHB Ligands: Design, Synthesis, and Binding Studies". J. Med. Chem. 51 (24): 8088–95. doi:10.1021/jm801112u. PMID 19053823.
^ Ticku MK, Mehta AK (October 2008). "Characterization and pharmacology of the GHB receptor". Annals of the New York Academy of Sciences 1139: 374–85. doi:10.1196/annals.1432.048. PMID 18991884.

Cell surface receptor: G protein-coupled receptors

Class A:
Rhodopsin like

Neurotransmitter

Adrenergic	α1 (A B D) α2 (A B C) β1 β2 β3

Purinergic	Adenosine (A1 A2A A2B A3) P2Y (1 2 4 5 6 8 9 10 11 12 13 14)

Serotonin	(all but 5-HT3) 5-HT1 (A B D E F) 5-HT2 (A B C) 5-HT (4 5A 6 7)

Other	Acetylcholine (M1 M2 M3 M4 M5) Dopamine (D1 D2 D3 D4 D5) Histamine (H1 H2 H3 H4) Melatonin (1A 1B 1C) TAAR (1 2 3 5 6 8 9)

Metabolites and
signaling molecules

Eicosanoid	CysLT (1 2) LTB4 (1 2) FPRL1 OXE Prostaglandin (DP (1 2), EP (1 2 3 4), FP) Prostacyclin Thromboxane

Other	Bile acid Cannabinoid (CB1 CB2, GPR (18 55 119)) EBI2 Estrogen Free fatty acid (1 2 3 4) Lactate Lysophosphatidic acid (1 2 3 4 5 6) Lysophospholipid (1 2 3 4 5 6 7 8) Niacin (1 2) Oxoglutarate PAF Sphingosine-1-phosphate (1 2 3 4 5) Succinate

Peptide

Neuropeptide	B/W (1 2) FF (1 2) S Y (1 2 4 5) Neuromedin (B U (1 2)) Neurotensin (1 2)

Other	Anaphylatoxin (C3a C5a) Angiotensin (1 2) Apelin Bombesin (BRS3 GRPR NMBR) Bradykinin (B1 B2) Chemokine Cholecystokinin (A B) Endothelin (A B) Formyl peptide (1 2 3) FSH Galanin (1 2 3) GHB receptor Gonadotropin-releasing hormone (1 2) Ghrelin Kisspeptin Luteinizing hormone/choriogonadotropin MAS (1 1L D E F G X1 X2 X3 X4) Melanocortin (1 2 3 4 5) MCHR (1 2) Motilin Opioid (Delta Kappa Mu Nociceptin & Zeta, but not Sigma) Orexin (1 2) Oxytocin Prokineticin (1 2) Prolactin-releasing peptide Relaxin (1 2 3 4) Somatostatin (1 2 3 4 5) Tachykinin (1 2 3) Thyrotropin Thyrotropin-releasing hormone Urotensin-II Vasopressin (1A 1B 2)

Miscellaneous

Orphan	GPR (1 3 4 6 12 15 17 18 19 20 21 22 23 25 26 27 31 32 33 34 35 37 39 42 44 45 50 52 55 61 62 63 65 68 75 77 78 81 82 83 84 85 87 88 92 101 103 109A 109B 119 120 132 135 137B 139 141 142 146 148 149 150 151 152 153 160 161 162 171 173 174 176 177 182 183)

Other	Adrenomedullin Olfactory Opsin (3 4 5 1LW 1MW 1SW RGR RRH) Protease-activated (1 2 3 4) SREB (1 2 3)

Class B: Secretin like

Orphan	GPR (56 64 97 98 110 111 112 113 114 115 116 123 124 125 126 128 133 143 144 155 157)

Other	Brain-specific angiogenesis inhibitor (1 2 3) Cadherin (1 2 3) Calcitonin CALCRL CD97 Corticotropin-releasing hormone (1 2) EMR (1 2 3) Glucagon (GR GIPR GLP1R GLP2R) Growth hormone releasing hormone PACAPR1 GPR Latrophilin (1 2 3 ELTD1) Methuselah-like proteins Parathyroid hormone (1 2) Secretin Vasoactive intestinal peptide (1 2)

Class C: Metabotropic
glutamate / pheromone

Taste	TAS1R (1 2 3) TAS2R (1 3 4 5 7 8 9 10 13 14 16 19 20 30 31 38 39 40 41 42 43 45 46 50 60)

Other	Calcium-sensing receptor GABA B (1 2) Glutamate receptor (Metabotropic glutamate (1 2 3 4 5 6 7 8)) GPRC6A GPR (156 158 179) RAIG (1 2 3 4)

Class F:
Frizzled / Smoothened

Frizzled	Frizzled (1 2 3 4 5 6 7 8 9 10)

Smoothened	Smoothened

B trdu: iter (nrpl/grfl/cytl/horl), csrc (lgic, enzr, gprc, igsr, intg, nrpr/grfr/cytr), itra (adap, gbpr, mapk), calc, lipd; path (hedp, wntp, tgfp+mapp, notp, jakp, fsap, hipp, tlrp)

v t e GHBR Ligands

Agonists	1,4-BD 4-Methyl-GHB Amisulpride GABOB GBL GHB GHV GVL NCS-356 NCS-435 Sulpiride Sultopride T-HCA UMB66 UMB68 UMB72 UMB86 HOCPCA

Antagonists	NCS-382

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GHB receptor

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