Nomenclature: α6

Family: GABAA receptors

Annotation status:  image of an orange circle Annotated and awaiting review. Please contact us if you can help with reviewing. 

Contents

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 4 453 5q34 GABRA6 gamma-aminobutyric acid (GABA) A receptor, alpha 6 3,5
Mouse 4 453 11 A5 Gabra6 gamma-aminobutyric acid (GABA) A receptor, subunit alpha 6 8
Rat 4 453 10q21 Gabra6 gamma-aminobutyric acid (GABA) A receptor, alpha 6 22
Previous and Unofficial Names
GABA(A) receptor, alpha 6
GABA(A) receptor subunit alpha-6
GABA-A receptor alpha-6 subunit
gamma-aminobutyric acid (GABA-A) receptor subunit alpha 6
gamma-aminobutyric acid (GABA-A) receptor, subunit alpha 6
gamma-aminobutyric acid A receptor, alpha 6
gamma-aminobutyric acid receptor subunit alpha-6
Gabra-6
alpha6
GABA-ARalpha6
Database Links
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
GeneCards
GenitoUrinary Development Molecular Anatomy Project
HomoloGene
Human Protein Reference Database
InterPro
KEGG Gene
OMIM
PharmGKB Gene
PhosphoSitePlus
Protein Ontology (PRO)
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniGene Hs.
UniProtKB
Wikipedia
Natural/Endogenous Ligand(s)
GABA
Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
piperidine-4-sulphonic acid Hs Full agonist - -
[Binds to: GABA site] low efficacy
[3H]muscimol Hs Full agonist - -
[Binds to: GABA site]
gaboxadol Hs Agonist - -
[Binds to: GABA site]
isoguvacine Hs Full agonist - -
[Binds to: GABA site]
muscimol Hs Full agonist - -
[Binds to: GABA site]
isonipecotic acid Hs Full agonist - -
[Binds to: GABA site] relatively high efficacy
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
[3H]gabazine Hs Antagonist - -
[Binds to: GABA site]
bicuculline Hs Antagonist - -
[Binds to: GABA site]
gabazine Hs Antagonist - -
[Binds to: GABA site]
Channel Blockers
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Use-dependent Affinity Units Concentration range (M) Voltage-dependent (mV) Reference
[35S]TBPS Hs - no - - - no
[Binds to: anion channel]
Not voltage dependent
picrotoxin ? - no - - - no

Not voltage dependent
TBPS Hs - no - - - no

Not voltage dependent
View species-specific channel blocker tables
Allosteric Regulators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Concentration range (M) Voltage-dependent (mV) Reference
5α-pregnan-3α-ol-20-one Hs Potentiation - - - no

Not voltage dependent
flumazenil Hs Partial agonist - - - no
[Binds to: benzodiazepine site] low affinity
Not voltage dependent
[18F]fluoroethylflumazenil Hs Antagonist - - - no
[Binds to: benzodiazepine site]
Not voltage dependent
bretazenil Hs Full agonist - - - no
[Binds to: benzodiazepine site]
Not voltage dependent
Ro15-4513 Hs Full agonist - - - no
[Binds to: benzodiazepine site]
Not voltage dependent
tetrahydrodeoxycorticosterone Hs Potentiation - - - no

Not voltage dependent
[11C]flumazenil Hs Partial agonist - - - no
[Binds to: benzodiazepine site] low affinity
Not voltage dependent
[3H]Ro154513 Hs Full agonist - - - no
[Binds to: benzodiazepine site]
Not voltage dependent
Zn2+ Hs Inhibition - - - no

Not voltage dependent
[3H]CGS8216 Hs Mixed - - - no
[Binds to: benzodiazepine site] agonist and antagonist
Not voltage dependent
Tissue Distribution
The α6 subunit is exclusively expressed in cerebellar and cochlear nucleus granule cells
Species:  Mouse
Technique:  in situ hybridisation, PCR.
References:  2,21
The α6 subunit is exclusively expressed in cerebellar and cochlear nucleus granule cells
Species:  Rat
Technique:  In situ hybridisation
References:  11-12,18,23
The α6 subunit is exclusively expressed in cerebellar and cochlear nucleus granule cells
Species:  Rat
Technique:  immunohistochemistry
References:  19
The α6 subunit of GABAA receptors is concentrated in both inhibitory Golgi synapses and excitatory mossy fiber synapses, but is located also extrasynaptically on cerebellar granule cells
Species:  Rat
Technique:  electron microscopy
References:  16-17
Physiological Consequences of Altering Gene Expression
A knockout of α6 subunits did not result in an overt phenotype, but the mice were more sensitive to the motor-impairing action of diazepam in an accelerating rotarod test than their wild-type counterparts. In addition, a selective post-translational loss of the δ subunit was apparent in cerebellar granule cells of the mice indicating that the δ subunit is co-assembled with the α6 subunit.
Species:  Mouse
Tissue:  Nervous system
Technique:  Knockout
References:  6-7,10
A knockout of α6 subunits did not cause cochlear histopathology, and cochlear responses suggested normal function of hair cells, afferent fibers, and efferent feedback.
Species:  Mouse
Tissue:  Nervous system
Technique:  Knockout
References:  13
A knockout of α6 subunits triggered some changes in the GABAA receptor composition of cerebellar granule cells as indicated by biochemical/immunological techniques and receptor binding studies, as well as a compensatory up-regulation of a potassium channel.
Species:  Mouse
Tissue:  Nervous system
Technique:  Knockout
References:  1,14-15
Biologically Significant Variants
Type:  Allelic variant
Species:  Mouse
Description:  The presence of four nucleotide changes and a three base-pair deletion in the GABAA α6-subunit promoter was identified in Sardinian alcohol non-preferring rats, selectively bred for their ethanol aversion. These rats also carry the R100Q α6 mutation. Results indicate that one or more of the mutations found in the 5´ flanking α6 region may be a consensus sequence for regulatory factors which are responsible for both basal and ethanol-induced α6 gene expression.
Amino acids:  100
References:  20
Type:  Point mutation.
Species:  Rat
Description:  In an alcohol-non-tolerant (ANT) rat line the α6 gene is expressed at wild-type levels but carries a point mutation generating an arginine-to-glutamine substitution at position 100. The resulting α6(Q100)β2γ2 receptors, in contrast to wild-type α6β2γ2 receptors, show diazepam-mediated potentiation of GABA-activated currents in oocytes and diazepam-sensitive binding of [3H]Ro15-4513 in vivo. These results explain the strong impairment of postural reflexes by diazepam in these rats. However, neither the mutant R100Q, nor wild type R100, expressed with β2γ2 in oocytes showed ethanol enhancement at motor incoordinating concentrations so the behavioural phenotype of alcohol hypersensitivity was not explained.
Amino acids:  100
References:  9
Type:  Allelic variant
Species:  Rat
Description:  The ‘point mutation’ R100Q [Korpi et al, 1993] has been demonstrated to be a naturally-occurring allelic variant in the α6 subunit gene, enriched in the ANT rat strain and also the Sardinian alcohol-preferring (P) rat strain mentioned by Saba et al (2005), but not (yet) demonstrated to produce the phenotype. This variant expressed in oocytes as α6(R100Q)β3δ showed hypersensitivity to enhancement by low millimolar ethanol compared to the already sensitive wild type α6β3δ and insensitive α6βγ2 rats expressing the allele (α6100QQ) were more sensitive to low dose ethanol impairment of rotarod behaviour in vivo than wild type (α6100RR) and more sensitive to low dose ethanol enhancement of tonic inhibitory currents recorded in cerebellar granule cells in brain slice patch clamp recordings in vitro.
Amino acids:  100
References:  4,9,20

REFERENCES

1. Brickley SG, Revilla V, Cull-Candy SG, Wisden W, Farrant M. (2001) Adaptive regulation of neuronal excitability by a voltage-independent potassium conductance. Nature409 (6816): 88-92. [PMID:11343119]

2. Drescher DG, Green GE, Khan KM, Hajela K, Beisel KW, Morley BJ, Gupta AK. (1993) Analysis of gamma-aminobutyric acidA receptor subunits in the mouse cochlea by means of the polymerase chain reaction. J. Neurochem.61 (3): 1167-70. [PMID:8395561]

3. Hadingham KL, Garrett EM, Wafford KA, Bain C, Heavens RP, Sirinathsinghji DJ, Whiting PJ. (1996) Cloning of cDNAs encoding the human gamma-aminobutyric acid type A receptor alpha 6 subunit and characterization of the pharmacology of alpha 6-containing receptors. Mol. Pharmacol.49 (2): 253-9. [PMID:8632757]

4. Hanchar HJ, Dodson PD, Olsen RW, Otis TS, Wallner M. (2005) Alcohol-induced motor impairment caused by increased extrasynaptic GABA(A) receptor activity. Nat. Neurosci.8 (3): 339-45. [PMID:15696164]

5. Hicks AA, Bailey ME, Riley BP, Kamphuis W, Siciliano MJ, Johnson KJ, Darlison MG. (1994) Further evidence for clustering of human GABAA receptor subunit genes: localization of the alpha 6-subunit gene (GABRA6) to distal chromosome 5q by linkage analysis. Genomics20 (2): 285-8. [PMID:8020978]

6. Homanics GE, Ferguson C, Quinlan JJ, Daggett J, Snyder K, Lagenaur C, Mi ZP, Wang XH, Grayson DR, Firestone LL. (1997) Gene knockout of the alpha6 subunit of the gamma-aminobutyric acid type A receptor: lack of effect on responses to ethanol, pentobarbital, and general anesthetics. Mol. Pharmacol.51 (4): 588-96. [PMID:9106623]

7. Jones A, Korpi ER, McKernan RM, Pelz R, Nusser Z, Mäkelä R, Mellor JR, Pollard S, Bahn S, Stephenson FA, Randall AD, Sieghart W, Somogyi P, Smith AJ, Wisden W. (1997) Ligand-gated ion channel subunit partnerships: GABAA receptor alpha6 subunit gene inactivation inhibits delta subunit expression. J. Neurosci.17 (4): 1350-62. [PMID:9006978]

8. Kato K. (1990) Novel GABAA receptor alpha subunit is expressed only in cerebellar granule cells. J. Mol. Biol.214 (3): 619-24. [PMID:2167378]

9. Korpi ER, Kleingoor C, Kettenmann H, Seeburg PH. (1993) Benzodiazepine-induced motor impairment linked to point mutation in cerebellar GABAA receptor. Nature361 (6410): 356-9. [PMID:7678923]

10. Korpi ER, Koikkalainen P, Vekovischeva OY, Mäkelä R, Kleinz R, Uusi-Oukari M, Wisden W. (1999) Cerebellar granule-cell-specific GABAA receptors attenuate benzodiazepine-induced ataxia: evidence from alpha 6-subunit-deficient mice. Eur. J. Neurosci.11 (1): 233-40. [PMID:9987027]

11. 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]

12. Lüddens H, Pritchett DB, Köhler M, Killisch I, Keinänen K, Monyer H, Sprengel R, Seeburg PH. (1990) Cerebellar GABAA receptor selective for a behavioural alcohol antagonist. Nature346 (6285): 648-51. [PMID:2166916]

13. Maison SF, Rosahl TW, Homanics GE, Liberman MC. (2006) Functional role of GABAergic innervation of the cochlea: phenotypic analysis of mice lacking GABA(A) receptor subunits alpha 1, alpha 2, alpha 5, alpha 6, beta 2, beta 3, or delta. J. Neurosci.26 (40): 10315-26. [PMID:17021187]

14. Mäkelä R, Uusi-Oukari M, Homanics GE, Quinlan JJ, Firestone LL, Wisden W, Korpi ER. (1997) Cerebellar gamma-aminobutyric acid type A receptors: pharmacological subtypes revealed by mutant mouse lines. Mol. Pharmacol.52 (3): 380-8. [PMID:9281599]

15. Nusser Z, Ahmad Z, Tretter V, Fuchs K, Wisden W, Sieghart W, Somogyi P. (1999) Alterations in the expression of GABAA receptor subunits in cerebellar granule cells after the disruption of the alpha6 subunit gene. Eur. J. Neurosci.11 (5): 1685-97. [PMID:10215922]

16. Nusser Z, Sieghart W, Somogyi P. (1998) Segregation of different GABAA receptors to synaptic and extrasynaptic membranes of cerebellar granule cells. J. Neurosci.18 (5): 1693-703. [PMID:9464994]

17. Nusser Z, Sieghart W, Stephenson FA, Somogyi P. (1996) The alpha 6 subunit of the GABAA receptor is concentrated in both inhibitory and excitatory synapses on cerebellar granule cells. J. Neurosci.16 (1): 103-14. [PMID:8613776]

18. 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]

19. Pirker S, Schwarzer C, Wieselthaler A, Sieghart W, Sperk G. (2000) GABA(A) receptors: immunocytochemical distribution of 13 subunits in the adult rat brain. Neuroscience101 (4): 815-50. [PMID:11113332]

20. Saba L, Porcella A, Sanna A, Congeddu E, Marziliano N, Mongeau R, Grayson D, Pani L. (2005) Five mutations in the GABA A alpha6 gene 5' flanking region are associated with a reduced basal and ethanol-induced alpha6 upregulation in mutated Sardinian alcohol non-preferring rats. Brain Res. Mol. Brain Res.137 (1-2): 252-7. [PMID:15950783]

21. Varecka L, Wu CH, Rotter A, Frostholm A. (1994) GABAA/benzodiazepine receptor alpha 6 subunit mRNA in granule cells of the cerebellar cortex and cochlear nuclei: expression in developing and mutant mice. J. Comp. Neurol.339 (3): 341-52. [PMID:8132866]

22. Wieland HA, Lüddens H, Seeburg PH. (1992) A single histidine in GABAA receptors is essential for benzodiazepine agonist binding. J. Biol. Chem.267 (3): 1426-9. [PMID:1346133]

23. 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]

To cite this database page, please use the following:

Richard Olsen, John A. Peters, Tim G. Hales, Werner Sieghart, Uwe Rudolph, Jeremy J. Lambert, Delia Belelli, Bernhard Luscher.
GABAA receptors: α6. Last modified on 14/03/2014. Accessed on 24/04/2014. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=409.

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