GABAB receptor

GABAB receptors (GABABR) are metabotropic transmembrane receptors for gamma-aminobutyric acid (GABA) that are linked via G-proteins to potassium 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 the GABAA IPSP. GABAB receptors are found in the central nervous system and the autonomic division of the peripheral nervous system.[2]

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

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.[3]

Functions

They can stimulate the opening of K+ channels which brings the neuron closer to the equilibrium potential of K+. This reduces the frequency of action potentials which reduces neurotransmitter release. Thus GABAB receptors are inhibitory receptors.

GABAB receptors also reduces the activity of adenylyl cyclase and Ca2+ channels by using G-proteins with Gi/G0 α subunits.[4]

GABAB receptors are involved in behavioral actions of ethanol,[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]

Structure

GABAB Receptors are similar in structure to and in the same receptor family with metabotropic glutamate receptors.[10] There are two subunits of the receptor, GABAB1 and GABAB2,[11] and these appear to assemble as heterodimers in neuronal membranes by linking up by their intracellular C termini.[10] In the mammalian brain, two predominant, differentially expressed isoforms of the GABAB1 are 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] In 2020, researchers characterized the structure of the full length GABAB receptor in different conformational states from inactive apo to fully active in complex with an inhibitory G protein. It was shown that unlike Class A and B GPCRs, phospholipids bind within the transmembrane bundles and surprisingly allosteric modulators bind at the interface of GABAB1 and GABAB2 subunits. [13][14][15]

Ligands
GABA
GHB
Lesogaberan

Agonists
CGP-7930

Positive Allosteric Modulators
Phaclofen
SCH-50911

Antagonists

See also

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.
  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.
  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 (2003). "Gamma-aminobutyric acid B receptor 1 mediates behavior-impairing actions of alcohol in Drosophila: adult RNA interference and pharmacological evidence". Proc Natl Acad Sci USA. 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. PMID 15564584.
  7. Dimitrijevic N, Dzitoyeva S, Satta R, Imbesi M, Yildiz S, Manev H (2005). "Drosophila GABA(B) receptors are involved in behavioral effects of gamma-hydroxybutyric acid (GHB)". Eur J Pharmacol. 519 (3): 246–52. doi:10.1016/j.ejphar.2005.07.016. PMID 16129424.
  8. Manev H, Dimitrijevic N (2004). "Drosophila model for in vivo pharmacological analgesia research". Eur J Pharmacol. 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 (2005). "Developmental role of GABAB(1) receptors in Drosophila". Brain Res Dev Brain Res. 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, Klemens; Huggel, Katharina; Heid, Jakob; Flor, Peter J.; Bischoff, Serge; Mickel, Stuart J.; McMaster, Gary; Angst, Christof; Bittiger, Helmut; Froestl, Wolfgang; Bettler, Bernhard (March 1997). "Expression cloning of GABA B receptors uncovers similarity to metabotropic glutamate receptors". Nature. 386 (6622): 239–246. doi:10.1038/386239a0. ISSN 1476-4687.
  13. Shaye, Hamidreza; Ishchenko, Andrii; Lam, Jordy Homing; Han, Gye Won; Xue, Li; Rondard, Philippe; Pin, Jean-Philippe; Katritch, Vsevolod; Gati, Cornelius; Cherezov, Vadim (2020-06-17). "Structural basis of the activation of a metabotropic GABA receptor". Nature: 1–6. doi:10.1038/s41586-020-2408-4. ISSN 1476-4687.
  14. Mao, Chunyou; Shen, Cangsong; Li, Chuntao; Shen, Dan-Dan; Xu, Chanjuan; Zhang, Shenglan; Zhou, Rui; Shen, Qingya; Chen, Li-Nan; Jiang, Zhinong; Liu, Jianfeng (2020-06-03). "Cryo-EM structures of inactive and active GABA B receptor". Cell Research: 1–10. doi:10.1038/s41422-020-0350-5. ISSN 1748-7838.
  15. Park, Jinseo; Fu, Ziao; Frangaj, Aurel; Liu, Jonathan; Mosyak, Lidia; Shen, Tong; Slavkovich, Vesna N.; Ray, Kimberly M.; Taura, Jaume; Cao, Baohua; Geng, Yong (2020-06-24). "Structure of human GABA B receptor in an inactive state". Nature: 1–6. doi:10.1038/s41586-020-2452-0. ISSN 1476-4687.
  16. Urwyler S, Mosbacher J, Lingenhoehl K, Heid J, Hofstetter K, Froestl W, Bettler B, Kaupmann K (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". Mol. Pharmacol. 60 (5): 963–71. doi:10.1124/mol.60.5.963. PMID 11641424.
  17. Adams CL, Lawrence AJ (2007). "CGP7930: a positive allosteric modulator of the GABAB receptor". CNS Drug Rev. 13 (3): 308–16. doi:10.1111/j.1527-3458.2007.00021.x. PMC 6494120. PMID 17894647.
  18. 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". J. Pharmacol. Exp. Ther. 326 (1): 306–14. doi:10.1124/jpet.108.139204. PMC 2574924. PMID 18445779.
  19. Urwyler S, Pozza MF, Lingenhoehl K, Mosbacher J, Lampert C, Froestl W, Koller M, Kaupmann K (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". J. Pharmacol. Exp. Ther. 307 (1): 322–30. doi:10.1124/jpet.103.053074. PMID 12954816.
  20. Giotti A, Luzzi S, Spagnesi S, Zilletti L (1983). "Homotaurine: a GABAB antagonist in guinea-pig ileum". Br. J. Pharmacol. 79: 855–62. doi:10.1111/j.1476-5381.1983.tb10529.x. PMC 2044932. PMID 6652358.
  21. Kimura T, Saunders PA, Kim HS, Rheu HM, Oh KW, Ho IK (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.
  22. Froestl W, Gallagher M, Jenkins H, Madrid A, Melcher T, Teichman S, Mondadori CG, Pearlman R (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.
  23. Bullock R (January 2005). "SGS-742 Novartis". Current Opinion in Investigational Drugs. 6 (1): 108–13. PMID 15675610.
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