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GABAA receptor β2 subunit

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Target not currently curated in GtoImmuPdb

Target id: 411

Nomenclature: GABAA receptor β2 subunit

Family: GABAA receptors

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 4 512 5q34 GABRB2 gamma-aminobutyric acid type A receptor subunit beta2 14,19
Mouse 4 512 11 25.08 cM Gabrb2 gamma-aminobutyric acid type A receptor subunit beta 2 10
Rat 4 474 10q21 Gabrb2 gamma-aminobutyric acid type A receptor subunit beta 2 30
Previous and Unofficial Names Click here for help
Gabrb-2 | gamma-aminobutyric acid receptor subunit beta-2 | gamma-aminobutyric acid (GABA) A receptor, beta 2 | gamma-aminobutyric acid (GABA) A receptor, subunit beta 2 | gamma-aminobutyric acid (GABA) A receptor | gamma-aminobutyric acid type A receptor beta2 subunit | gamma-aminobutyric acid type A receptor beta 2 subunit
Database Links Click here for help
Alphafold P47870 (Hs), P63137 (Mm), P63138 (Rn)
CATH/Gene3D 2.70.170.10
ChEMBL Target CHEMBL1920 (Hs), CHEMBL4296059 (Mm), CHEMBL4296056 (Rn), CHEMBL2111343 (Rn), CHEMBL4296063 (Rn), CHEMBL3883322 (Rn), CHEMBL2111365 (Rn), CHEMBL2095167 (Rn), CHEMBL4296055 (Rn), CHEMBL2111327 (Rn)
DrugBank Target P47870 (Hs), P47870 (Hs)
Ensembl Gene ENSG00000145864 (Hs), ENSMUSG00000007653 (Mm), ENSRNOG00000003680 (Rn)
Entrez Gene 2561 (Hs), 14401 (Mm), 25451 (Rn)
Human Protein Atlas ENSG00000145864 (Hs)
KEGG Gene hsa:2561 (Hs), mmu:14401 (Mm), rno:25451 (Rn)
OMIM 600232 (Hs)
Pharos P47870 (Hs)
RefSeq Nucleotide NM_021911 (Hs), NM_000813 (Hs), NM_008070 (Mm), NM_012957 (Rn)
RefSeq Protein NP_068711 (Hs), NP_000804 (Hs), NP_032096 (Mm), NP_037089 (Rn)
UniProtKB P47870 (Hs), P63137 (Mm), P63138 (Rn)
Wikipedia GABRB2 (Hs)
Natural/Endogenous Ligands Click here for help
GABA

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Channel Blockers
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Use-dependent Value Parameter Concentration range (M) Voltage-dependent (mV) Reference
picrotoxin Small molecule or natural product Click here for species-specific activity table Hs - no - - - no
⤷
Not voltage dependent
TBPS Small molecule or natural product Click here for species-specific activity table Hs - no - - - no
⤷
Not voltage dependent
Tissue Distribution Click here for help
Entorhinal cortex
Species:  Human
Technique:  In situ hybridisation
References:  13
Hippocampus:-
Among the β subunits, the β2 is the least abundant in the hippocampus. Marked labelling of a great number of interneurons throughout the hippocampal formation is observed. Only weak staining is seen in dendrites of pyramidal neurons (preferentially in CA1) and of granule cells (molecular layer of dentate gyrus). The β2 antibody intensely labels the perikarya and the dendritic trees of pyramidal-shaped basket cells in the hilus of the dentate gyrus and basket cells located in the CA1 pyramidal cell layer. A band of neurons located within the middle and inner molecular layer of the dentate gyrus also shows β2-immunoreactivity.
Expression level:  Low
Species:  Rat
Technique:  Immunohistochemistry
References:  23
Basal ganglia and limbic areas:-
Staining for the β2 subunit is considerably stronger in the globus pallidus, entopeduncular nucleus, ventral pallidum and substantia nigra pars reticulata, than in the striatum, nucleus accumbens and olfactory tubercle.
Expression level:  High
Species:  Rat
Technique:  Immunohistochemistry
References:  20
Spinal cord, dorsal root ganglia :-
In situ hybridization indicated that the transcript levels of the β2 subunit differed markedly among cells of layers IV-VIII, and X. Transcripts of β2 are quite restricted in the dorsal root ganglia.
Expression level:  High
Species:  Rat
Technique:  In situ hybridisation
References:  15,28
Whole brain:-
In situ hybridization signals for the β2 subunit are strongest in the olfactory bulb, the neocortex and pyriform cortex, globus pallidus, septum, thalamus, and Purkinje and granule cells of the cerebellum. Signals are weaker in the hippocampus, amygdala, midbrain and substantia nigra, and nearly absent in the hypothalamus.
Expression level:  High
Species:  Rat
Technique:  In situ hybridisation
References:  12,16,29
Whole brain:-
The β2 subunit is widely distributed throughout the brain, especially in the cerebral cortex, the pallidum, thalamic nuclei (except in the reticular nucleus). In the hippocampus, β2 antibodies label interneurons, in the cerebellum, β2 subunits are strongly labelled in granule cells. β2 subunits are found in many interneurons throughout the brain and are distributed similarly to α1 and γ2 subunits, especially in the internal granular layer of the olfactory bulb, where α1 and β2-subunits are contained in similar neurons and dendrites and the polymorph cell layer and CA3 sector of the hippocampus, where antibodies for α1, β2, and γ2 subunits label the same type of neurons. Also the globus pallidus and several thalamic nuclei display similar staining patterns for the α1 and β2 subunits.
Expression level:  High
Species:  Rat
Technique:  Immunohistochemistry
References:  17
The distribution of the 3 subunit largely matches that of 1. Immunoreactivity of the 3 subunit, however, in general is stronger than that of 1. 3 immunoreactivity is most prominent in the molecular layer of the dentate gyrus and intense in the strata oriens and radiatum of CA1 and CA3. In CA2 considerably less 3 than 1 immunoreactivity was observed. The layers oif principal neurons and the terminal field of mossy fibres were spared for 1 and 3.
Species:  Rat
Technique:  Immunohistochemistry
References:  25
Thalamic nuclei, basal ganglia, sensory motor cortex:-
The expression pattern of the β2 subunit is identical to that of α1. The majority of thalamic nuclei display a high intensity signal, but in the paracentral nucleus, the lateral habenula, and the nucleus reticularis thalami no signal is detected. In the basal ganglia, the β2 subunit is strongly expressed in all nuclei. In sensory cortex there is laminar and sub-laminar-specific expression.
Species:  Rhesus macaque
Technique:  In situ hybridisation
References:  8-9,11
Tissue Distribution Comments
Using In situ hybridization the expression patterns in rhesus monkey show:-
Expression in thalamic nuclei, basal ganglia and sensory motor cortex. The expression pattern of the β2 subunit is identical to that of α1. The majority of thalamic nuclei display a high intensity signal, but in the paracentral nucleus, the lateral habenula, and the nucleus reticularis thalami no signal is detected. In the basal ganglia, the β2 subunit is strongly expressed in all nuclei. In sensory cortex there is laminar and sub-laminar-specific expression [8-9,11]
Physiological Consequences of Altering Gene Expression Click here for help
Total GABAA receptor density is decreased by more than 50%. In mice lacking the β2 subunit (β2(-/-)) and the expression level of all six α subunits is reduced by between approximately 40 and 70%. However, β2(-/-) mice breed and develop normally, and do not display spontaneous seizures. β2(-/-) animals do not display any gross deficits in motor function, but do exhibit greater spontaneous locomotor activity. β2(-/-) mice show decreased sleep time in response to the benzodiazepine agonist flurazepam, the β2/3 subunit-preferring intravenous general anaesthetic etomidate, and the δ subunit-preferring GABAA agonist, THIP. Male, but not female, knockout mice are less sensitive to the hypnotic action of ethanol.
Species:  Mouse
Tissue:  Nervous system
Technique:  Gene knockout
References:  3,24
β2-Subunit knock-in mice possessing a point mutation (i.e., N265S) in the β2 subunit display a reduction in sedation induced by the anticonvulsant loreclezole. In such animals loreclezole fails to provide significant protection against pentylenetetrazole-induced seizures and demonstrates reduced efficacy against amygdala-kindled seizures.
Species:  Mouse
Tissue:  Nervous system
Technique:  Knock-in (β2N265S)
References:  5
Deletion of the β2 subunit causes severe disruption of phasic inhibitory neurotransmission and reduces the tonic current mediated by GABA in ventrobasal (VB) neurones of the thalamus. Sensitivity of the tonic current to enhancement by the β2/3 subunit-selective agent etomidate is also reduced. In VB neurones of β2-subunit knock-in mice carrying a point mutation (i.e., N265S) in the β2 subunit, prolongation of the decay of mIPSCs and enhancement of the tonic current is significantly reduced. Such data suggest that GABAA receptors containing the β2 subunit are expressed at synapses and extrasynaptic compartments in VB neurones.
Species:  Mouse
Tissue:  Nervous system
Technique:  Knockout and knock-in (β2N265S)
References:  2
Deletion of the β2 subunit causes a significant reduction in the inhibitory tonic current mediated by GABA in hippocampal dentate gyrus granule cells (DGGCs) and attenuates the increase of this current induced by the &delta subunit-preferring agonist, THIP. mIPSCs are not influenced by deletion of the Gabrb2 gene. In DGGCs of β2-subunit knock-in mice carrying a point mutation (i.e., N265S) in the β2 subunit, which eliminates the action of etomidate via this subunit, enhancement of the tonic current by the β2/3 subunit-selective agent etomidate is significantly reduced, whereas this manipulation has little effect on the prolongation of mIPSCs produced by this anaesthetic. Such data indicate that the latter effect is mediated via the β3 subunit and that GABAA receptors containing the β2 subunit are expressed at DGGC synapses at low levels and are localised to extrasynaptic compartments.
Species:  Mouse
Tissue:  Nervous system
Technique:  Knockout and knock-in (β2N265S)
References:  7
β2-Subunit knock-in mice possessing a point mutation (i.e., N265S) in the β2 subunit display a reduction in sedation induced by a subanaesthetic dose of the general anaesthetic etomidate, but normal anaesthesia in response to a higher dose of the compound. This suggests that many aspects of etomidate anaesthesia are mediated not by β2- but by β3-containing GABAA receptors. Such mice also have a reduced hypothermic response to anaesthetic doses of etomidate compared with wild-type controls and regain normothermia more rapidly. Sub-anaesthetic doses of etomidate produce hypothermia in wild-type mice, but not in the mutant animals. Moreover, loss of the sedative action of etomidate in mice carrying the N265S mutation unmasks an anxiolytic action of subanaesthetic doses of the compound as indicated by increased spontaneous activity.
Species:  Mouse
Tissue:  Nervous system
Technique:  Knock-in (β2N265S)
References:  4,18
Biologically Significant Variants Click here for help
Type:  Splice variant
Species:  Human
Description:  This variant (β2S) lacks a 114 bp insertion (exon 10) in the coding sequence resulting in a protein that is 38 amino acid residues (360-397) shorter than the full length variant. This variant lacks a phosphorylation consensus sequence for calmodulin-dependent protein kinase II at Thr365 within the large intracellular loop.
Amino acids:  474
Nucleotide accession:  NM_000813
Protein accession:  NP_000804
References:  14,19
Type:  Splice variant
Species:  Human
Description:  Full length ‘canonical’ variant containing exon 10 (β2L)
Amino acids:  512
Nucleotide accession:  NM_000813
Protein accession:  NP_068711
References:  10,14,19,30
Biologically Significant Variant Comments
Recombinant GABAA receptors expressed in HEK293 human cells containing the β2L subunit are reported to undergo steeper current rundown upon repetitive GABA activation than receptors containing the β2S isoform [31-32]. Additional β2S splice variants (i.e. β2S1 and β2S2) have been described [32]. Splice variants of the β2 subunit may by related to psychotic disorders [31-32].
General Comments
The β2, along with the β3, subunit imparts selective sensitivity compared to β1 subunit with regard to positive allosteric regulation by the anticonvulsant loreclezole [18,27] and a structural analogue, the intravenous general anaesthetic etomidate [1] as well as the structurally distinct intravenous general anaesthetic, propofol [1,21]. A number of non-steroidal anti-inflammatory agents, including mefenamic acid, also selectively potentiate the activity of receptors containing β2, versus β1, subunits [6,22]. The β2 subunit along with the β1 subunit show about 10-fold lower sensitivity than the β3 subunit toward modulation by low-dose (20 mM) ethanol, when expressed in Xenopus oocytes with α4 and δ subunits [26].

References

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1. Belelli D, Lambert JJ, Peters JA, Wafford K, Whiting PJ. (1997) The interaction of the general anesthetic etomidate with the gamma-aminobutyric acid type A receptor is influenced by a single amino acid. Proc Natl Acad Sci USA, 94 (20): 11031-6. [PMID:9380754]

2. Belelli D, Peden DR, Rosahl TW, Wafford KA, Lambert JJ. (2005) Extrasynaptic GABAA receptors of thalamocortical neurons: a molecular target for hypnotics. J Neurosci, 25 (50): 11513-20. [PMID:16354909]

3. Blednov YA, Jung S, Alva H, Wallace D, Rosahl T, Whiting PJ, Harris RA. (2003) Deletion of the alpha1 or beta2 subunit of GABAA receptors reduces actions of alcohol and other drugs. J Pharmacol Exp Ther, 304 (1): 30-6. [PMID:12490572]

4. Cirone J, Rosahl TW, Reynolds DS, Newman RJ, O'Meara GF, Hutson PH, Wafford KA. (2004) Gamma-aminobutyric acid type A receptor beta 2 subunit mediates the hypothermic effect of etomidate in mice. Anesthesiology, 100 (6): 1438-45. [PMID:15166563]

5. Groves JO, Guscott MR, Hallett DJ, Rosahl TW, Pike A, Davies A, Wafford KA, Reynolds DS. (2006) The role of GABAbeta2 subunit-containing receptors in mediating the anticonvulsant and sedative effects of loreclezole. Eur J Neurosci, 24 (1): 167-74. [PMID:16882014]

6. Halliwell RF, Thomas P, Patten D, James CH, Martinez-Torres A, Miledi R, Smart TG. (1999) Subunit-selective modulation of GABAA receptors by the non-steroidal anti-inflammatory agent, mefenamic acid. Eur J Neurosci, 11 (8): 2897-905. [PMID:10457186]

7. Herd MB, Haythornthwaite AR, Rosahl TW, Wafford KA, Homanics GE, Lambert JJ, Belelli D. (2008) The expression of GABAA beta subunit isoforms in synaptic and extrasynaptic receptor populations of mouse dentate gyrus granule cells. J Physiol (Lond.), 586 (4): 989-1004. [PMID:18079158]

8. Huntsman MM, Leggio MG, Jones EG. (1996) Nucleus-specific expression of GABA(A) receptor subunit mRNAs in monkey thalamus. J Neurosci, 16 (11): 3571-89. [PMID:8642403]

9. Huntsman MM, Woods TM, Jones EG. (1995) Laminar patterns of expression of GABA-A receptor subunit mRNAs in monkey sensory motor cortex. J Comp Neurol, 362 (4): 565-82. [PMID:8636468]

10. Kamatchi GL, Kofuji P, Wang JB, Fernando JC, Liu Z, Mathura JR, Burt DR. (1995) GABAA receptor beta 1, beta 2, and beta 3 subunits: comparisons in DBA/2J and C57BL/6J mice. Biochim Biophys Acta, 1261 (1): 134-42. [PMID:7893750]

11. Kultas-Ilinsky K, Leontiev V, Whiting PJ. (1998) Expression of 10 GABA(A) receptor subunit messenger RNAs in the motor-related thalamic nuclei and basal ganglia of Macaca mulatta studied with in situ hybridization histochemistry. Neuroscience, 85 (1): 179-204. [PMID:9607711]

12. Laurie DJ, Seeburg PH, Wisden W. (1992) The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. II. Olfactory bulb and cerebellum. J Neurosci, 12 (3): 1063-76. [PMID:1312132]

13. Longson D, Longson CM, Jones EG. (1997) Localization of CAM II kinase-alpha, GAD, GluR2 and GABA(A) receptor subunit mRNAs in the human entorhinal cortex. Eur J Neurosci, 9 (4): 662-75. [PMID:9153573]

14. McKinley DD, Lennon DJ, Carter DB. (1995) Cloning, sequence analysis and expression of two forms of mRNA coding for the human beta 2 subunit of the GABAA receptor. Brain Res Mol Brain Res, 28 (1): 175-9. [PMID:7707873]

15. Persohn E, Malherbe P, Richards JG. (1991) In situ hybridization histochemistry reveals a diversity of GABAA receptor subunit mRNAs in neurons of the rat spinal cord and dorsal root ganglia. Neuroscience, 42 (2): 497-507. [PMID:1654537]

16. Persohn E, Malherbe P, Richards JG. (1992) Comparative molecular neuroanatomy of cloned GABAA receptor subunits in the rat CNS. J Comp Neurol, 326 (2): 193-216. [PMID:1336019]

17. Pirker S, Schwarzer C, Wieselthaler A, Sieghart W, Sperk G. (2000) GABA(A) receptors: immunocytochemical distribution of 13 subunits in the adult rat brain. Neuroscience, 101 (4): 815-50. [PMID:11113332]

18. Reynolds DS, Rosahl TW, Cirone J, O'Meara GF, Haythornthwaite A, Newman RJ, Myers J, Sur C, Howell O, Rutter AR et al.. (2003) Sedation and anesthesia mediated by distinct GABA(A) receptor isoforms. J Neurosci, 23 (24): 8608-17. [PMID:13679430]

19. Russek SJ, Farb DH. (1994) Mapping of the beta 2 subunit gene (GABRB2) to microdissected human chromosome 5q34-q35 defines a gene cluster for the most abundant GABAA receptor isoform. Genomics, 23 (3): 528-33. [PMID:7851879]

20. Schwarzer C, Berresheim U, Pirker S, Wieselthaler A, Fuchs K, Sieghart W, Sperk G. (2001) Distribution of the major gamma-aminobutyric acid(A) receptor subunits in the basal ganglia and associated limbic brain areas of the adult rat. J Comp Neurol, 433 (4): 526-49. [PMID:11304716]

21. Siegwart R, Jurd R, Rudolph U. (2002) Molecular determinants for the action of general anesthetics at recombinant alpha(2)beta(3)gamma(2)gamma-aminobutyric acid(A) receptors. J Neurochem, 80 (1): 140-8. [PMID:11796752]

22. Smith AJ, Oxley B, Malpas S, Pillai GV, Simpson PB. (2004) Compounds exhibiting selective efficacy for different beta subunits of human recombinant gamma-aminobutyric acid A receptors. J Pharmacol Exp Ther, 311 (2): 601-9. [PMID:15210837]

23. Sperk G, Schwarzer C, Tsunashima K, Fuchs K, Sieghart W. (1997) GABA(A) receptor subunits in the rat hippocampus I: immunocytochemical distribution of 13 subunits. Neuroscience, 80 (4): 987-1000. [PMID:9284055]

24. Sur C, Wafford KA, Reynolds DS, Hadingham KL, Bromidge F, Macaulay A, Collinson N, O'Meara G, Howell O, Newman R et al.. (2001) Loss of the major GABA(A) receptor subtype in the brain is not lethal in mice. J Neurosci, 21 (10): 3409-18. [PMID:11331371]

25. Wagstaff J, Chaillet JR, Lalande M. (1991) The GABAA receptor beta 3 subunit gene: characterization of a human cDNA from chromosome 15q11q13 and mapping to a region of conserved synteny on mouse chromosome 7. Genomics, 11 (4): 1071-8. [PMID:1664410]

26. Wallner M, Hanchar HJ, Olsen RW. (2003) Ethanol enhances alpha 4 beta 3 delta and alpha 6 beta 3 delta gamma-aminobutyric acid type A receptors at low concentrations known to affect humans. Proc Natl Acad Sci USA, 100 (25): 15218-23. [PMID:14625373]

27. Wingrove PB, Wafford KA, Bain C, Whiting PJ. (1994) The modulatory action of loreclezole at the gamma-aminobutyric acid type A receptor is determined by a single amino acid in the beta 2 and beta 3 subunit. Proc Natl Acad Sci USA, 91 (10): 4569-73. [PMID:8183949]

28. Wisden W, Gundlach AL, Barnard EA, Seeburg PH, Hunt SP. (1991) Distribution of GABAA receptor subunit mRNAs in rat lumbar spinal cord. Brain Res Mol Brain Res, 10 (2): 179-83. [PMID:1649370]

29. Wisden W, Laurie DJ, Monyer H, Seeburg PH. (1992) The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. I. Telencephalon, diencephalon, mesencephalon. J Neurosci, 12 (3): 1040-62. [PMID:1312131]

30. Ymer S, Schofield PR, Draguhn A, Werner P, Köhler M, Seeburg PH. (1989) GABAA receptor beta subunit heterogeneity: functional expression of cloned cDNAs. EMBO J, 8 (6): 1665-70. [PMID:2548852]

31. Zhao C, Xu Z, Chen J, Yu Z, Tong KL, Lo WS, Pun FW, Ng SK, Tsang SY, Xue H. (2006) Two isoforms of GABA(A) receptor beta2 subunit with different electrophysiological properties: Differential expression and genotypical correlations in schizophrenia. Mol Psychiatry, 11 (12): 1092-105. [PMID:16983389]

32. Zhao C, Xu Z, Wang F, Chen J, Ng SK, Wong PW, Yu Z, Pun FW, Ren L, Lo WS et al.. (2009) Alternative-splicing in the exon-10 region of GABA(A) receptor beta(2) subunit gene: relationships between novel isoforms and psychotic disorders. PLoS ONE, 4 (9): e6977. [PMID:19763268]

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