γ‐Aminobutyric Acid (GABA) Receptors


γ‐Aminobutyric acid (GABA) is the most widely distributed inhibitory neurotransmitter in the central nervous system of adult vertebrates. Virtually all neurons are sensitive to GABA through its actions on either the diverse set of ionotropic type A receptors (GABAARs), the putative heterodimeric metabotropic type B receptors (GABABRs) or the ionotropic retina‐enriched type C receptors (GABACRs).

Keywords: neurotransmitter receptor; ancestral gene clusters; anxiety; epilepsy; neurotransmission

Figure 1.

Schematic model of the GABAA receptor. (a) The GABAA receptor is displayed as five subunits that join together to form an integral ion channel that is selective for chloride (Cl) and gated by the binding of GABA to its putative site on the receptor at the αβ interface. The direction of chloride flow is dependent upon the concentration gradient of chloride ions inside and outside of the cell. This gradient is controlled developmentally by the expression of specific chloride transporters. Sites for multiple modulatory agents are indicated, including those for barbiturates (Barbs), zinc (Zn2+), alcohol (EtOH) and benzodiazepines (BZD). (Reproduced from Franks NP and Lieb WR (1997) Nature 389: 334–335 with permission from Nature Publishing.) (b) Each subunit possesses extracellular N‐ and C‐terminal domains. There are four putative membrane‐spanning domains (M1–M4), depicted as cylinders. Between the M3 and M4 domains there is a large intracellular domain that contains consensus sequences for phosphorylation by various kinases. The subunit combination shown here, α1αxβ2βyγ2, appears to be widely distributed in the vertebrate brain. Other combinations are also possible. Sites for phosphorylation were chosen based on the primary amino acid sequences of the rat GABAA receptor subunits. The α1, α3, α4, α5 and α6 sequences contain sites for protein kinase C (PC). The α4 contains sites for protein kinase A (PA) and the α6 two sites for protein kinase A (not illustrated). The β2 possesses a protein kinase A consensus site sequence as shown. The β1 and β3 contain both protein kinase A and protein kinase C sites. As shown, the γ2 has the potential for phosphorylation by protein kinase C and protein tyrosine kinases. The alternative splice variant γ2L contains an additional protein kinase C consensus sequence. Like the γ2, the γ1 and γ3 have amino acid sequences that may serve as recognition sites for protein tyrosine kinase. (Reproduced from Rabow et al. (1995) with permission from Synapse, Wiley‐Liss, Inc., see Further Reading.)

Figure 2.

The family of subunits for GABA‐gated receptors. (a) The products of 18 distinct genes have been identified as originating from a common ancestor. Fourteen of these products are specific to the GABAA family and two of them, ρ1 and ρ2, to the GABAC family. Classification is based on pharmacological profile. The tree was generated using the GCG program PAUP search (the GCG interface for phylogenetic analysis using parsimony). Per cent similarity in amino acid composition was determined using the GAP program in GCG (gap creation penalty of eight and extension penalty of two) and results are displayed in the right‐hand column. Identical positions of α genes are as noted. (b) Signature pattern for all neurotransmitter‐gated ion channels. This consensus pattern is found in all of the subunits for GABA‐gated receptors. The region is located in the N‐terminal extracellular domain that is flanked by two cysteine residues believed to be linked by a disulfide bond. In GABAA β subunits, the residue N‐terminal to the 3′ cysteine is an N‐glycosylated asparagine (GCG, ProfileScan).

Figure 3.

Schematic representation of the genomic organization of GABAA receptor gene clusters in the human genome. (a) Estimates of genomic distance between genes on chromosomes 4 and 5 were obtained from interphase mapping. Distance measurements for the genes on chromosome 15 were obtained by restriction fragment length fingerprinting and interphase flourescent in situ hybridization (FISH) mapping and by restriction fragment length analysis with field inversion gel electrophoresis. (Reproduced from Russek (1999) with permission from GENE, © Elsevier Publishing.) (b) Gene organization is conserved for the GABAA receptor gene clusters on human chromosomes 4, 5, 15 and X. Orientation of subunit genes is indicated by the direction of the arrows. The schematic is not drawn to scale. The most current cytogenetic localization of the gene cluster is indicated next to the chromosome number. Information for chromosomes 4 and 5 is presented in Russek, 1999. Information for chromosomes 15 and X is from the literature (Greger et al., 1995; Levin et al., 1996; Wilke et al., 1997). (Reproduced from Russek (1999) with permission from GENE, © Elsevier Publishing.)

Figure 4.

Schematic representation of the GABAB receptor indicating the dimeric nature of the structure. R1a: the a isoform of GABABR1; R1b: the b isoform of GABABR1; α, β and γ: G‐protein subunits; Kir: inwardly rectifying K+ channel; AC: adenylate cyclase; ATP: adenosine triphosphate; cAMP: cyclic adenosine monophosphate. (Reproduced with permission from Bowery NG and Enna SJ (2000) Journal of Pharmacology and Experimental Therapeutics 292: 2–7.)

Figure 5.

Sequence alignment of the human GABABR2 indicates a new member of the metabotropic GABA receptor gene family. Identification of unique transcripts, expressed‐sequence tags (ESTs), for the human GABABR2 and GABABR1 genes. The human ESTs were identified using a search with the rat GABABR1 amino acid sequence as the query. The GABAB receptors share 19 amino acid identities in the region aligned, indicated in bold type. Four of these amino acids are also identical in the mGluRs and are indicated by bold type. The region aligned is 57 amino acids between the putative transmembrane domains 1 and 3. The region corresponding to transmembrane 2 (TMII) is indicated below the alignment by a dashed line, three amino acids in transmembrane domains 1 and 3 are indicated by three dashes to the left and the right respectively. The sequences in the amino acid alignment shown are human EST GABABR2, accession number T07621; human EST GABABR1, X90542; rat GABABR1, Y10369; and human metabotropic glutamate receptors (mGluR) 1–8: mGluR1, U31215; mGluR2, L35318; mGluR3, X77748; mGluR4, U92457; mGluR5, D28538; mGluR6, U82083; mGluR7, U92458 and mGluR8, U92459. (Reproduced with permission from Martin SC, et al. (1999) Molecular Cellular Neuroscience 13: 180–191.)



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Further Reading

Blein S, Hawrot E and Barlow P (2000) The metabotropic GABA receptor: molecular insights and their functional consequences (review). Cellular and Molecular Life Sciences 57: 635–650.

Enz R and Cutting GR (1998) Molecular composition of GABAC receptors (review). Vision Research 38: 1431–1441.

Kirkness EF and Fraser CM (1993) A strong promoter element is located between alternative exons of a gene encoding the human γ‐aminobutyric acid‐type A receptor β3 (GABRB3). Journal of Biological Chemistry 268: 4420–4428.

Laurie DJ, Wisden W and Seeburg PH (1992) The distribution of thirteen GABAA receptor subunit mRNAs in the rat brain. III. Embryonic and postnatal development. Journal of Neuroscience 11: 4151–4172.

Leinekugel X, Khalilov I, McLean H, et al. (1999) GABA is the principal fast‐acting excitatory transmitter in the neonatal brain. Advances in Neurology 79: 189–201.

Mandel G and McKinnon D (1993) Molecular basis of neural‐specific gene expression. Annual Review of Neuroscience 16: 323–345.

McLean PJ, Bandyopadhyay S, Shepktor D, Russek SJ and Farb DH (2000) A minimal promoter for the GABAAR α6 subunit gene controls tissue specificity. Journal of Neurochemistry 74: 1858–1869.

Rabow LE, Russek SJ and Farb DH (1995) From ion currents to genomic analysis: recent advances in GABAA receptor research (review). Synapse 21:189–274.

Russek SJ, Bandyopadhyay S and Farb DH (2000) An initiator in the human GABAA receptor β1 subunit gene couples neurotransmitter action to transcription. Proceedings of the National Academy of Sciences of the United States of America 97: 8600–8605.

Sinnet D, Wagstaff J, Glatt K, et al. (1993) High‐resolution mapping of the γ‐aminobutyric acid receptor β3 and α5 gene cluster on chromosome 15q11–q13, and localization of breakpoints in two Angelman syndrome patients. American Journal of Human Genetics 52: 1216–1229.

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Russek, Shelley J(Sep 2006) γ‐Aminobutyric Acid (GABA) Receptors. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005907]