Misplaced Pages

GABA_B receptors (GABA_BR) are G-protein coupled receptors for gamma-aminobutyric acid (GABA), therefore making them metabotropic receptors, that are linked via G-proteins to potassium channels. The changing potassium concentrations hyperpolarize the cell at the end of an action potential. The reversal potential of the GABA_B-mediated IPSP (inhibitory postsynaptic potential) is −100 mV, which is much more hyperpolarized than the GABA_A IPSP. GABA_B receptors are found in the central nervous system and the autonomic division of the peripheral nervous system.

The receptors were first named in 1981 when their distribution in the CNS was determined, which was determined by Norman Bowery and his team using radioactively labelled baclofen.

Functions

GABA_BRs stimulate the opening of K channels, specifically GIRKs, which brings the neuron closer to the equilibrium potential of K. This reduces the frequency of action potentials which reduces neurotransmitter release. Thus GABA_B receptors are inhibitory receptors.

GABA_B receptors also reduces the activity of adenylyl cyclase and Ca channels by using G-proteins with G_i/G₀ α subunits.

GABA_B receptors are involved in behavioral actions of ethanol, gamma-hydroxybutyric acid (GHB), and possibly in pain. Recent research suggests that these receptors may play an important developmental role.

Structure

GABA_B Receptors are similar in structure to and in the same receptor family with metabotropic glutamate receptors. There are two subunits of the receptor, GABA_B1 and GABA_B2, and these appear to assemble as obligate heterodimers in neuronal membranes by linking up by their intracellular C termini. In the mammalian brain, two predominant, differentially expressed isoforms of the GABA_B1 are transcribed from the Gabbr1 gene, GABA_B(1a) and GABA_B(1b), which are conserved in different species including humans. This might potentially offer more complexity in terms of the function due to different composition of the receptor. Cryo-electron microscopy structures of the full length GABA_B receptor in different conformational states from inactive apo to fully active have been obtained. Unlike Class A and B GPCRs, phospholipids bind within the transmembrane bundles and allosteric modulators bind at the interface of GABA_B1 and GABA_B2 subunits.

Ligands

Agonists

• GABA
• Baclofen is a GABA analogue which acts as a selective agonist of GABA_B receptors, and is used as a muscle relaxant. However, it can aggravate absence seizures, and so is not used in epilepsy.
• gamma-Hydroxybutyrate (GHB)
• Phenibut
• 4-Fluorophenibut
• Isovaline
• 3-Aminopropylphosphinic acid
• Lesogaberan
• SKF-97541: 3-Aminopropyl(methyl)phosphinic acid, 10× more potent than baclofen as GABA_B agonist, but also GABA_A-ρ antagonist
• Taurine
• CGP-44532

Positive Allosteric Modulators

• CGP-7930
• BHFF
• Fendiline
• BHF-177
• BSPP
• GS-39783

Antagonists

• Homotaurine
• Ginsenosides
• 2-OH-saclofen
• Saclofen
• Phaclofen
• SCH-50911
• 2-Phenethylamine
• CGP-35348
• CGP-52432: 3-(amino]propyl) diethoxymethyl)phosphinic acid, CAS# 139667-74-6
• CGP-55845: (2S)-3-(amino-2-hydroxypropyl)(phenylmethyl)phosphinic acid, CAS# 149184-22-5
• SGS-742

See also

• GABA receptor
• GABA_A receptor

References

1. Chen K, Li HZ, Ye N, Zhang J, Wang JJ (October 2005). "Role of GABAB receptors in GABA and baclofen-induced inhibition of adult rat cerebellar interpositus nucleus neurons in vitro". Brain Research Bulletin. 67 (4): 310–8. doi:10.1016/j.brainresbull.2005.07.004. PMID 16182939. S2CID 6433030.
2. Hyland NP, Cryan JF (2010). "A Gut Feeling about GABA: Focus on GABA(B) Receptors". Frontiers in Pharmacology. 1: 124. doi:10.3389/fphar.2010.00124. PMC 3153004. PMID 21833169.
3. Hill DR, Bowery NG (March 1981). "3H-baclofen and 3H-GABA bind to bicuculline-insensitive GABA B sites in rat brain". Nature. 290 (5802): 149–52. Bibcode:1981Natur.290..149H. doi:10.1038/290149a0. PMID 6259535. S2CID 4335907.
4. Rang HP, Dale MM, Ritter JM, Flower RJ, Henderson G (2016). Rang and Dale's Pharmacology (8th ed.). Elsevier, Churchill Livingstone. p. 462. ISBN 978-0-7020-5362-7. OCLC 903234097.
5. Dzitoyeva S, Dimitrijevic N, Manev H (April 2003). "Gamma-aminobutyric acid B receptor 1 mediates behavior-impairing actions of alcohol in Drosophila: adult RNA interference and pharmacological evidence". Proceedings of the National Academy of Sciences of the United States of America. 100 (9): 5485–90. Bibcode:2003PNAS..100.5485D. doi:10.1073/pnas.0830111100. PMC 154371. PMID 12692303.
6. Ariwodola OJ, Weiner JL (November 2004). "Ethanol potentiation of GABAergic synaptic transmission may be self-limiting: role of presynaptic GABA(B) receptors". The Journal of Neuroscience. 24 (47): 10679–86. doi:10.1523/JNEUROSCI.1768-04.2004. PMC 6730127. PMID 15564584.
7. Dimitrijevic N, Dzitoyeva S, Satta R, Imbesi M, Yildiz S, Manev H (September 2005). "Drosophila GABA(B) receptors are involved in behavioral effects of gamma-hydroxybutyric acid (GHB)". European Journal of Pharmacology. 519 (3): 246–52. doi:10.1016/j.ejphar.2005.07.016. PMID 16129424.
8. Manev H, Dimitrijevic N (May 2004). "Drosophila model for in vivo pharmacological analgesia research". European Journal of Pharmacology. 491 (2–3): 207–8. doi:10.1016/j.ejphar.2004.03.030. PMID 15140638.
9. Dzitoyeva S, Gutnov A, Imbesi M, Dimitrijevic N, Manev H (August 2005). "Developmental role of GABAB(1) receptors in Drosophila". Brain Research. Developmental Brain Research. 158 (1–2): 111–4. doi:10.1016/j.devbrainres.2005.06.005. PMID 16054235.
10. ^ MRC (Medical Research Council). 2003. Glutamate receptors: Structures and functions. University of Brisotol Centre for Synaptic Plasticity.
11. Purves D, Augustine GJ, Fitzpatrick D, Katz LC, LaMantia AS, McNamara JO, Williams SM (2001). "7. Neurotransmitter Receptors and Their Effects". Neuroscience (Second ed.). Sinauer Associates, Inc.
12. ^ Kaupmann K, Huggel K, Heid J, Flor PJ, Bischoff S, Mickel SJ, et al. (March 1997). "Expression cloning of GABA(B) receptors uncovers similarity to metabotropic glutamate receptors". Nature. 386 (6622): 239–46. Bibcode:1997Natur.386..239K. doi:10.1038/386239a0. PMID 9069281. S2CID 4345443.
13. Shaye H, Stauch B, Gati C, Cherezov V (May 2021). "Molecular mechanisms of metabotropic GABA_B receptor function". Science Advances. 7 (22): eabg3362. Bibcode:2021SciA....7.3362S. doi:10.1126/sciadv.abg3362. PMC 8163086. PMID 34049877.
14. Shaye H, Ishchenko A, Lam JH, Han GW, Xue L, Rondard P, et al. (August 2020). "Structural basis of the activation of a metabotropic GABA receptor". Nature. 584 (7820): 298–303. Bibcode:2020Natur.584..298S. doi:10.1038/s41586-020-2408-4. PMC 8020835. PMID 32555460.
15. Papasergi-Scott MM, Robertson MJ, Seven AB, Panova O, Mathiesen JM, Skiniotis G (June 2020). "Structures of metabotropic GABAB receptor". Nature. 584 (7820): 310–314. Bibcode:2020Natur.584..310P. doi:10.1038/s41586-020-2469-4. PMC 7429364. PMID 32580208.
16. Mao C, Shen C, Li C, Shen DD, Xu C, Zhang S, et al. (June 2020). "B receptor". Cell Research. 30 (7): 564–573. doi:10.1038/s41422-020-0350-5. PMC 7343782. PMID 32494023. S2CID 219183617.
17. Park J, Fu Z, Frangaj A, Liu J, Mosyak L, Shen T, et al. (June 2020). "B receptor in an inactive state". Nature. 584 (7820): 304–309. doi:10.1038/s41586-020-2452-0. PMC 7725281. PMID 32581365. S2CID 220050861.
18. Kim Y, Jeong E, Jeong JH, Kim Y, Cho Y (November 2020). "Structural Basis for Activation of the Heterodimeric GABA_B Receptor". Journal of Molecular Biology. 432 (22): 5966–5984. doi:10.1016/j.jmb.2020.09.023. PMID 33058878. S2CID 222841520.
19. Shen C, Mao C, Xu C, Jin N, Zhang H, Shen DD, et al. (June 2021). "Structural basis of GABA_B receptor-G_i protein coupling". Nature. 594 (7864): 594–598. Bibcode:2021Natur.594..594S. doi:10.1038/s41586-021-03507-1. PMC 8222003. PMID 33911284.
20. Urwyler S, Mosbacher J, Lingenhoehl K, Heid J, Hofstetter K, Froestl W, et al. (November 2001). "Positive allosteric modulation of native and recombinant gamma-aminobutyric acid(B) receptors by 2,6-Di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) and its aldehyde analog CGP13501". Molecular Pharmacology. 60 (5): 963–71. doi:10.1124/mol.60.5.963. PMID 11641424.
21. Adams CL, Lawrence AJ (2007). "CGP7930: a positive allosteric modulator of the GABAB receptor". CNS Drug Reviews. 13 (3): 308–16. doi:10.1111/j.1527-3458.2007.00021.x. PMC 6494120. PMID 17894647.
22. Paterson NE, Vlachou S, Guery S, Kaupmann K, Froestl W, Markou A (July 2008). "Positive modulation of GABA(B) receptors decreased nicotine self-administration and counteracted nicotine-induced enhancement of brain reward function in rats". The Journal of Pharmacology and Experimental Therapeutics. 326 (1): 306–14. doi:10.1124/jpet.108.139204. PMC 2574924. PMID 18445779.
23. Urwyler S, Pozza MF, Lingenhoehl K, Mosbacher J, Lampert C, Froestl W, et al. (October 2003). "N,N'-Dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (GS39783) and structurally related compounds: novel allosteric enhancers of gamma-aminobutyric acidB receptor function". The Journal of Pharmacology and Experimental Therapeutics. 307 (1): 322–30. doi:10.1124/jpet.103.053074. PMID 12954816. S2CID 26152839.
24. Giotti A, Luzzi S, Spagnesi S, Zilletti L (August 1983). "Homotaurine: a GABAB antagonist in guinea-pig ileum". British Journal of Pharmacology. 79 (4): 855–62. doi:10.1111/j.1476-5381.1983.tb10529.x. PMC 2044932. PMID 6652358.
25. Kimura T, Saunders PA, Kim HS, Rheu HM, Oh KW, Ho IK (January 1994). "Interactions of ginsenosides with ligand-bindings of GABA(A) and GABA(B) receptors". General Pharmacology. 25 (1): 193–9. doi:10.1016/0306-3623(94)90032-9. PMID 8026706.
26. Froestl W, Gallagher M, Jenkins H, Madrid A, Melcher T, Teichman S, et al. (October 2004). "SGS742: the first GABA(B) receptor antagonist in clinical trials". Biochemical Pharmacology. 68 (8): 1479–87. doi:10.1016/j.bcp.2004.07.030. PMID 15451390.
27. Bullock R (January 2005). "SGS-742 Novartis". Current Opinion in Investigational Drugs. 6 (1): 108–13. PMID 15675610.

External links

• Genes on human chromosome 6
• Genes on human chromosome 9
• G protein-coupled receptors
• GABA