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GABABreceptor

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(Redirected fromGABA-B receptor)
gamma-aminobutyric acid (GABA) B receptor, 1
Identifiers
SymbolGABBR1
NCBI gene2550
HGNC4070
OMIM603540
RefSeqNM_021905
UniProtQ9UBS5
Other data
LocusChr. 6p21.3
Search for
StructuresSwiss-model
DomainsInterPro
gamma-aminobutyric acid (GABA) B receptor, 2
Identifiers
SymbolGABBR2
Alt. symbolsGPR51
NCBI gene9568
HGNC4507
OMIM607340
RefSeqNM_005458
UniProtO75899
Other data
LocusChr. 9q22.1-22.3
Search for
StructuresSwiss-model
DomainsInterPro

GABABreceptors(GABABR) areG-protein coupled receptorsforgamma-aminobutyric acid(GABA), therefore making themmetabotropic receptors,that are linked viaG-proteinstopotassium channels.[1]The changing potassium concentrations hyperpolarize the cell at the end of an action potential. The reversal potential of the GABAB-mediated IPSP (inhibitory postsynaptic potential) is −100 mV, which is much more hyperpolarized than theGABAAIPSP. GABABreceptors are found in thecentral nervous systemand theautonomicdivision of theperipheral nervous system.[2]

The receptors were first named in 1981 when their distribution in the CNS was determined, which was determined byNorman Boweryand his team using radioactively labelledbaclofen.[3]

Functions

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GABABRs stimulate the opening ofK+channels,specificallyGIRKs,which brings theneuroncloser to theequilibrium potentialof K+.This reduces the frequency ofaction potentialswhich reducesneurotransmitterrelease.[citation needed]Thus GABABreceptors are inhibitory receptors.

GABABreceptors also reduces the activity ofadenylyl cyclaseandCa2+channelsby using G-proteins withGi/G0α subunits.[4]

GABABreceptors are involved in behavioral actions ofethanol,[5][6]gamma-hydroxybutyric acid(GHB),[7]and possibly in pain.[8]Recent research suggests that these receptors may play an important developmental role.[9]

Receptor dimer, inactive apo state, cartoon representation

Structure

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GABABReceptors are similar in structure to and in the same receptor family withmetabotropic glutamate receptors.[10]There are two subunits of the receptor,GABAB1andGABAB2,[11]and these appear to assemble as obligateheterodimersin neuronal membranes by linking up by their intracellularC termini.[10]In the mammalian brain, two predominant, differentially expressedisoformsof the GABAB1are transcribed from the Gabbr1 gene, GABAB(1a)and GABAB(1b),which are conserved in different species including humans.[12]This might potentially offer more complexity in terms of the function due to different composition of the receptor.[12]Cryo-electron microscopystructures of the full length GABABreceptor in different conformational states from inactiveapoto fully active have been obtained. Unlike Class A and B GPCRs, phospholipids bind within the transmembrane bundles and allosteric modulators bind at the interface ofGABAB1andGABAB2subunits.[13][14][15][16][17][18][19]

Ligands

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GABA
GHB
Lesogaberan

Agonists

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CGP-7930

Positive Allosteric Modulators

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Phaclofen
SCH-50911

Antagonists

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See also

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References

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  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.PMID16182939.S2CID6433030.
  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.PMC3153004.PMID21833169.
  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.PMID6259535.S2CID4335907.
  4. ^Rang HP, Dale MM, Ritter JM, Flower RJ, Henderson G (2016).Rang and Dale's Pharmacology(8th ed.). Elsevier, Churchill Livingstone. p. 462.ISBN978-0-7020-5362-7.OCLC903234097.
  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.PMC154371.PMID12692303.
  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.PMC6730127.PMID15564584.
  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.PMID16129424.
  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.PMID15140638.
  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.PMID16054235.
  10. ^abMRC (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. ^abKaupmann 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.PMID9069281.S2CID4345443.
  13. ^Shaye H, Stauch B, Gati C, Cherezov V (May 2021)."Molecular mechanisms of metabotropic GABABreceptor function ".Science Advances.7(22): eabg3362.Bibcode:2021SciA....7.3362S.doi:10.1126/sciadv.abg3362.PMC8163086.PMID34049877.
  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.PMC8020835.PMID32555460.
  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.PMC7429364.PMID32580208.
  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.PMC7343782.PMID32494023.S2CID219183617.
  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.PMC7725281.PMID32581365.S2CID220050861.
  18. ^Kim Y, Jeong E, Jeong JH, Kim Y, Cho Y (November 2020)."Structural Basis for Activation of the Heterodimeric GABABReceptor ".Journal of Molecular Biology.432(22): 5966–5984.doi:10.1016/j.jmb.2020.09.023.PMID33058878.S2CID222841520.
  19. ^Shen C, Mao C, Xu C, Jin N, Zhang H, Shen DD, et al. (June 2021)."Structural basis of GABABreceptor-Giprotein coupling ".Nature.594(7864): 594–598.Bibcode:2021Natur.594..594S.doi:10.1038/s41586-021-03507-1.PMC8222003.PMID33911284.
  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.PMID11641424.
  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.PMC6494120.PMID17894647.
  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.PMC2574924.PMID18445779.
  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.PMID12954816.S2CID26152839.
  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.PMC2044932.PMID6652358.
  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.PMID8026706.
  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.PMID15451390.
  27. ^Bullock R (January 2005). "SGS-742 Novartis".Current Opinion in Investigational Drugs.6(1): 108–13.PMID15675610.
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