image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates. 

γ3

Family: GABAA receptors

Contents:
Gene and Protein Information
Previous and Unofficial Names
Database Links
Tissue Distribution
Physiological Consequences of Altering Gene Expression
Clinically-Relevant Mutations and Pathophysiology
Biologically Significant Variants
General Comments
References
Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 4 467 15q12 GABRG3 gamma-aminobutyric acid (GABA) A receptor, gamma 3 5,7
Mouse 4 467 7 C Gabrg3 gamma-aminobutyric acid (GABA) A receptor, subunit gamma 3 22
Rat 4 467 1q22 Gabrg3 gamma-aminobutyric acid (GABA) A receptor, gamma 3 12
Structural Information Comments
The data for tabulated are for the full length isoform of the human β3 subunit. A shorter alternatively spliced isoform lacks six amino acid residues and a consensus sequence for phosphorylation by PKC in the large intracellular M3-M4 loop [18].
Previous and Unofficial Names
gamma 3
GABRG-3
Q99928
B230362M20Rik
GABA(G) receptor, gamma 3
GABA(A) receptor subunit gamma-3
GABA-alpha receptor gamma-3 subunit
gamma-aminobutyric acid (GABA) A receptor, subunit gamma 3
gamma-aminobutyric acid A receptor, gamma 3
gamma-aminobutyric acid receptor subunit gamma-3
Database Links
ChEMBL Target 12040 (Hs), 11495 (Mm), 13062 (Rn)
Ensembl ENSG00000182256 (Hs), ENSMUSG00000055026 (Mm), ENSRNOG00000014862 (Rn)
Entrez Gene 2567 (Hs), 14407 (Mm), 79211 (Rn)
GeneCards GABRG3 (Hs)
GenitoUrinary Development Molecular Anatomy Project Gabrg3 (Mm)
HomoloGene 22444 (Hs)
Human Protein Reference Database 02579 (Hs)
InterPro Q99928 (Hs), P27681 (Mm), P28473 (Rn)
KEGG Gene hsa:2567 (Hs), mmu:14407 (Mm), rno:79211 (Rn)
OMIM 600233 (Hs)
PharmGKB Gene PA28502 (Hs)
PhosphoSitePlus Q99928 (Hs), P27681 (Mm)
Protein Ontology (PRO) PRO:000007779 (Hs)
RefSeq Nucleotide NM_033223 (Hs), NM_008074 (Mm), NM_024370 (Rn)
RefSeq Protein NP_150092 (Hs), NP_032100 (Mm), NP_077346 (Rn)
TreeFam ENSG00000182256 (Hs), ENSMUSG00000055026 (Mm), ENSRNOG00000014862 (Rn)
UniGene Hs. 569475 (Hs)
UniProt Q99928 (Hs), P27681 (Mm), P28473 (Rn)
Wikipedia γ3
GABAA receptors
Search for 3D structures on the PDB
Search by keyword: GABAA receptors γ3 Search by accession number: P27681, P28473, Q99928
Natural/Endogenous Ligand(s)
GABA
Tissue Distribution
Total brain and cerebellum:-
The γ3 subunit was found to associate with β2/3, α1, α2, α3, α4, and α6 subunits in extracts from total brain and cerebellum, respectively.
Expression level:  Low
Species:  Rat
Technique:  Immuno affinity purification
References:  20
Adult brain:-
The adult rat brain shows low but significant immunoreactivity for the γ3 subunit in olfactory system (glomerular layer, mitral cell layer, acessory bulb, anterior olfactory bulb, olfactory tubercle), cerebral cortex (throughout neocortex, insular cortex, piriform cortex, enthorihinal cortex, endopiriform cortex, tenia tecta, claustrum), basal ganglia (striatum, nucleus acumbens, globus pallidus, ventral pallidum, subthalamus), septal and basal forebrain (lateral, septal nucleus, septohippocampal nucleus,medial septal nucleus, diagonal band), hippocampus (strata oriens and radiatum of CA1 and CA3 regions, subiculum, para- and presubiculum), thalamus/ epithalamus /subthalamus (all nuclei), amygdala (all nuclei), hypothalamus (supraoptic nucleus, medial and lateral mammilliary nucleus), molecular layer of cerebellar cortex, midbrain and pons (nucleus of the optic tract, pretectal nuclei,deep mesenphalic nuclei, most of superior and inferior culliculi, pedunculopontine tegmental nucleus, lateral superior olive), medulla (parvoventricular nucleus, pargigantocellular nucleus, rostroventrolateral reticular nucleus, inferior olivary complex, cuneate nucleus), cranial nerve nuclei.
Expression level:  Low
Species:  Rat
Technique:  Immunohistochemistry
References:  17
Cortex, hippocampus:-
Expression of the γ3 subunit in cortex and hippocampus was first detected around birth and peaked around postnatal day 6 (homogenously across cortical layers), dropping off to near background levels by P12. Lower levels of expression were found in the developing thalamus (midline thalamic nuclei, reticular thalamus and medial geniculate) starting from embryonic day 17 and trailing off by postnatal day 6. Low levels were also detected in the caudate nucleus and globus pallidus. In the celebellum, the γ3 subunit mRNA was transiently detected around E17. Expression is highest in E14-17 intestine.
Expression level:  Medium
Species:  Rat
Technique:  In situ hybridisation
References:  13
Adult brain:-
Low levels of mRNA have been described in layers II/III, IV and V/VI of the cortex, CA1 and CA3 pyramidal cells, dentate gyrus granule cells, caudate putamen, nucleus acumbens, claustrum, all nuclei of the thalamus (with significantly higher expression in the medial geniculate nucleus), medial preoptic area of the hypothalamus, red nucleus of the midbrain, central nucleus of inferior colliculi, pars reticulata and pars comacta of substantia nigra, and granule cells of the cerebellum
Expression level:  Low
Species:  Rat
Technique:  In situ hybridisation
References:  23
Adult brain:-
Somewhat higher immunoreactivity for the γ3 subunit was detected in the following brain regions: olfactory bulb (external plexiform layer), cerebral cortex (perirhinal cortex), substantia nigra, substantia innominata, bed nucleus stria terminalis, hypothalamus (medial and lateral preoptic area, anterior hypothalamic area, paraventricular hypothalamic nucleus, periventricular nucleus, tuber cinereum area, arcuate nucleus, median eminence, ventromedial nucleus, dorsomedial nucelus, dorsal hypothalamic area, supramammillary nucleus), cerebellum (Purkinje cells, cerebellar nuclei), red nucleus, retrorubal field, ventral tegmental area, interpeduncular nucleus, superior culliculs (intemediate and deep layers), periaqueductal gray, dorsal and medial raphe nucleus, ventral nucleus of the lateral lemniscus, parabigeminal nucleus, pontine nuclei, reticulotegmental nucleus pons, parabrachial nucleus, pontine reticular nucleus caudal part, nucleus of the trapezoid body, medulla (gigantocellular nucleus, medullary reticular nucleus), vestibular spinal nucleus, nucleus of the solitary tract.
Expression level:  Medium
Species:  Rat
Technique:  Immunohistochemistry
References:  17
Tissue Distribution Comments
The protein sequences tabulated above represent immature polypeptides that include a 17 AA signal peptide that is absent in the mature polypeptide
Physiological Consequences of Altering Gene Expression
The GABRG3 gene maps to a GABAA receptor subunit gene cluster that includes GABRA5 and GABRB3 and is deleted in a neurological mutant of the p locus. However, compound heterozygous mutant mice that lack a functional copy of the Gabrg3 gene only are without an overt behavioral or brain morphological phenotype. Detailed behavioral analyses of mice lacking selectively the Gabrg3 gene have not been done.
Species:  Mouse
Tissue:  in vivo
Technique:  mapping of pink-eyed dilution (p) locus mutants
References:  3,5,16
Overexpression of the γ3 subunit results in the formation of benzodiazepine sensitive GABAA receptors. Moreover, upon overexpression the γ3 subunit can contribute to the formation of GABAA receptors that are clustered at postsynaptic sites. This was best evident in the absence of the γ2 subunit (Gabrg3 KO mice).
Species:  Mouse
Tissue:  in vivo
Technique:  Transgenic expression of the γ3 subunit under control of a human beta-actin gene promoter and an SV40 poly A signal
References:  1
Autism and autism spectrum disorders
Species:  Human
Tissue: 
Technique:  Naturally occurring copy number variations, deletions and duplications of chromosome 15q11-q13 containing the GABRG3-GABRA5-GABRB3 gene cluster
References:  2,4,9-11,14,19,21
Physiological Consequences of Altering Gene Expression Comments
The specific contribution of the GABRG3 gene deletion to autism and autism spectrum disorder phenotypes associated with chromosome 15q11-q13 copy number variations is currently not known. Loss of paternally or maternally inherited deletions of the same chromosomal region lead to Prader-Willy and Angelman syndrome, respectivley, which are principally attributed to loss of function of the UBE3A gene in this same chromosmal segement.
Clinically-Relevant Mutations and Pathophysiology
Disease:  Susceptibility to autism, chromosome 15q11-q13 duplication syndrome
OMIM:  608636
Orphanet:  106
Role:  Mental retardation in 75%, seizures in 15-30%, EEG abnormalities in 20-50%, impaired social interactions, impaired use of nonverbal behaviors, such as eye-to-eye gaze, facial expression, body posture, and gestures, impaired ability to form peer relationships, impaired language development. Lack of spontaneous play, restrictive behavior, interests, and activities, stereotyped, repetitive behavior, inflexible adherence to routines or rituals, increased serum serotonin in 25%, onset by 3 years of age

Male to female ratio 4:1

Occurs in 2-5 per 10,000 individuals
References:  2,4,9-11,15,19,21
Click column headers to sort
Type Species Molecular location Description Reference
Other Human 15q11-q13 2,4,9-11,15,19,21
Clinically-Relevant Mutations and Pathophysiology Comments
Autism and autism spectrum disorder are associated with copy number variation and epigenetic dysregulation of the 15q11-q13 gene cluster [10]. In particular, the expression of non-imprinted GABAA receptor subunit genes is significantly reduced specifically in the female 15q11-13 dupication brain without detectable methylation differences [2,4,9]. Whether alterations specifically of the GABRG3 gene dosage contribute to the behavioral disease phenotype is not known currently.
Biologically Significant Variants
GABRG3, transcript variant 2
Nucleotide accession:  NM_033223 
Protein accession:  NP_150092 
Amino acids:  473
Type:  Splice variant.
Species:  Human
References:  18
GABRG3, transcript variant 1
Nucleotide accession:  NM_033223 
Protein accession:  NP_150092 
Amino acids:  467
Type:  Splice variant
Species:  Human
References:  7
Gabrg3
Nucleotide accession:  NM_024370 
Protein accession:  NP_077346 
Amino acids:  467
Type:  Splice variant.
Species:  Rat
References:  8,12
Gabrg3
Nucleotide accession:  NM_008074 
Protein accession:  NP_032100 
Amino acids:  467
Type:  Splice variant.
Species:  Mouse
References:  22
Biologically Significant Variant Comments
Human transcript variant 2 represents a minor (<1%) alternatively spliced form of the GABRG3 gene. It reflects usage of an alternative spliced donor site that result in extension of exon nine by six amino acids and adds the consensus sequence of a PKC phosphorylation site. This extension maps to the cytoplasmic loop region between the 3rd and 4th transmembrane domain of the gamma 3 subunit [18]. Amino acid numbers tabulated include a 17 AA signal sequence that is absent in the mature polypeptides.
General Comments
The γ3 subunit is most abundant in the developing brain. Although there is significant γ3 subunit immunoreactivity detectable in brain of adult mice, the loss of 94% of benzodiazepine binding sites in Gabrg3 KO mice [6] and estimates that approx 80% of GABAA receptors are sensitive to benzodizepines, indicates that the γ3 subunit contributes to less than 5% of postnatal GABAA receptors. The same conclusion can be drawn from immunoaffinity purification experiments of γ3 subunit containing GABAA receptors[20].

REFERENCES

Show »

1. Baer, K; Essrich, C; Benson, JA; Benke, D; Bluethmann, H; Fritschy, JM; Lüscher, B. (1999) Postsynaptic clustering of gamma-aminobutyric acid type A receptors by the gamma3 subunit in vivo. Proc. Natl. Acad. Sci. U.S.A., 96 (22): 12860-5. [PMID:10536013]

2. Cook, EH; Lindgren, V; Leventhal, BL; Courchesne, R; Lincoln, A; Shulman, C; Lord, C; Courchesne, E. (1997) Autism or atypical autism in maternally but not paternally derived proximal 15q duplication. Am. J. Hum. Genet., 60 (4): 928-34. [PMID:9106540]

3. Culiat, CT; Stubbs, LJ; Montgomery, CS; Russell, LB; Rinchik, EM. (1994) Phenotypic consequences of deletion of the gamma 3, alpha 5, or beta 3 subunit of the type A gamma-aminobutyric acid receptor in mice. Proc. Natl. Acad. Sci. U.S.A., 91 (7): 2815-8. [PMID:8146195]

4. Filipek, PA; Juranek, J; Smith, M; Mays, LZ; Ramos, ER; Bocian, M; Masser-Frye, D; Laulhere, TM; Modahl, C; Spence, MA; et al.. (2003) Mitochondrial dysfunction in autistic patients with 15q inverted duplication. Ann. Neurol., 53 (6): 801-4. [PMID:12783428]

5. Greger, V; Knoll, JH; Woolf, E; Glatt, K; Tyndale, RF; DeLorey, TM; Olsen, RW; Tobin, AJ; Sikela, JM; Nakatsu, Y. (1995) The gamma-aminobutyric acid receptor gamma 3 subunit gene (GABRG3) is tightly linked to the alpha 5 subunit gene (GABRA5) on human chromosome 15q11-q13 and is transcribed in the same orientation. Genomics, 26 (2): 258-64. [PMID:7601451]

6. Günther, U; Benson, J; Benke, D; Fritschy, JM; Reyes, G; Knoflach, F; Crestani, F; Aguzzi, A; Arigoni, M; Lang, Y. (1995) Benzodiazepine-insensitive mice generated by targeted disruption of the gamma 2 subunit gene of gamma-aminobutyric acid type A receptors. Proc. Natl. Acad. Sci. U.S.A., 92 (17): 7749-53. [PMID:7644489]

7. Hadingham, KL; Wafford, KA; Thompson, SA; Palmer, KJ; Whiting, PJ. (1995) Expression and pharmacology of human GABAA receptors containing gamma 3 subunits. Eur. J. Pharmacol., 291 (3): 301-9. [PMID:8719414]

8. Herb, A; Wisden, W; Lüddens, H; Puia, G; Vicini, S; Seeburg, PH. (1992) The third gamma subunit of the gamma-aminobutyric acid type A receptor family. Proc. Natl. Acad. Sci. U.S.A., 89 (4): 1433-7. [PMID:1311098]

9. Hogart, A; Leung, KN; Wang, NJ; Wu, DJ; Driscoll, J; Vallero, RO; Schanen, NC; LaSalle, JM. (2009) Chromosome 15q11-13 duplication syndrome brain reveals epigenetic alterations in gene expression not predicted from copy number. J. Med. Genet., 46 (2): 86-93. [PMID:18835857]

10. Hogart, A; Nagarajan, RP; Patzel, KA; Yasui, DH; Lasalle, JM. (2007) 15q11-13 GABAA receptor genes are normally biallelically expressed in brain yet are subject to epigenetic dysregulation in autism-spectrum disorders. Hum. Mol. Genet., 16 (6): 691-703. [PMID:17339270]

11. Itsara, A; Cooper, GM; Baker, C; Girirajan, S; Li, J; Absher, D; Krauss, RM; Myers, RM; Ridker, PM; Chasman, DI; et al.. (2009) Population analysis of large copy number variants and hotspots of human genetic disease. Am. J. Hum. Genet., 84 (2): 148-61. [PMID:19166990]

12. Knoflach, F; Rhyner, T; Villa, M; Kellenberger, S; Drescher, U; Malherbe, P; Sigel, E; Möhler, H. (1991) The gamma 3-subunit of the GABAA-receptor confers sensitivity to benzodiazepine receptor ligands. FEBS Lett., 293 (1-2): 191-4. [PMID:1660002]

13. Laurie, DJ; Wisden, W; Seeburg, PH. (1992) The distribution of thirteen GABAA receptor subunit mRNAs in the rat brain. III. Embryonic and postnatal development. J. Neurosci., 12 (11): 4151-72. [PMID:1331359]

14. Miller, A. D. and Blaha, C. D. (2005) Midbrain muscarinic receptor mechanisms underlying regulation of mesoaccumbens and nigrostriatal dopaminergic transmission in the rat. Eur J Neurosci, 21: 1837-1846. [PMID:15869479]

15. Miller, DT; Shen, Y; Weiss, LA; Korn, J; Anselm, I; Bridgemohan, C; Cox, GF; Dickinson, H; Gentile, J; Harris, DJ; et al.. (2009) Microdeletion/duplication at 15q13.2q13.3 among individuals with features of autism and other neuropsychiatric disorders. J. Med. Genet., 46 (4): 242-8. [PMID:18805830]

16. Nakatsu, Y; Tyndale, RF; DeLorey, TM; Durham-Pierre, D; Gardner, JM; McDanel, HJ; Nguyen, Q; Wagstaff, J; Lalande, M; Sikela, JM. (1993) A cluster of three GABAA receptor subunit genes is deleted in a neurological mutant of the mouse p locus. Nature, 364 (6436): 448-50. [PMID:8392662]

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. Poulsen, CF; Christjansen, KN; Hastrup, S; Hartvig, L. (2000) Identification and cloning of a gamma 3 subunit splice variant of the human GABA(A) receptor. Brain Res. Mol. Brain Res., 78 (1-2): 201-3. [PMID:10891602]

19. Thomas, JA; Johnson, J; Peterson Kraai, TL; Wilson, R; Tartaglia, N; LeRoux, J; Beischel, L; McGavran, L; Hagerman, RJ. (2003) Genetic and clinical characterization of patients with an interstitial duplication 15q11-q13, emphasizing behavioral phenotype and response to treatment. Am. J. Med. Genet. A, 119A (2): 111-20. [PMID:12749048]

20. Tögel, M; Mossier, B; Fuchs, K; Sieghart, W. (1994) gamma-Aminobutyric acidA receptors displaying association of gamma 3-subunits with beta 2/3 and different alpha-subunits exhibit unique pharmacological properties. J. Biol. Chem., 269 (17): 12993-8. [PMID:8175718]

21. van Bon, BW; Mefford, HC; Menten, B; Koolen, DA; Sharp, AJ; Nillesen, WM; Innis, JW; de Ravel, TJ; Mercer, CL; Fichera, M; et al.. (2009) Further delineation of the 15q13 microdeletion and duplication syndromes: a clinical spectrum varying from non-pathogenic to a severe outcome. J. Med. Genet., 46 (8): 511-23. [PMID:19372089]

22. Wilson-Shaw, D; Robinson, M; Gambarana, C; Siegel, RE; Sikela, JM. (1991) A novel gamma subunit of the GABAA receptor identified using the polymerase chain reaction. FEBS Lett., 284 (2): 211-5. [PMID:1647983]

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:

Bernhard Luscher.
GABAA receptors: γ3. Last modified on 16/02/2012. Accessed on 20/05/2013. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=415.


Contact us | Print | Back to top | Help