Figure 1. Schematic model of the GABA_A receptor. (a) The GABA_A 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 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, 1x2y2, 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 GABA_A receptor subunits. The 1, 3, 4, 5 and 6 sequences contain sites for protein kinase C (P_C). The 4 contains sites for protein kinase A (P_A) and the 6 two sites for protein kinase A (not illustrated). The 2 possesses a protein kinase A consensus site sequence as shown. The 1 and 3 contain both protein kinase A and protein kinase C sites. As shown, the 2 has the potential for phosphorylation by protein kinase C and protein tyrosine kinases. The alternative splice variant 2L contains an additional protein kinase C consensus sequence. Like the 2, the 1 and 3 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 GABA_A family and two of them, 1 and 2, to the GABA_C 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 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 GABA_A 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 GABA_A 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 GABA_A 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 GABA_B receptor indicating the dimeric nature of the structure. R1a: the a isoform of GABA_BR1; R1b: the b isoform of GABA_BR1; , and : 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 GABA_BR2 indicates a new member of the metabotropic GABA receptor gene family. Identification of unique transcripts, expressed-sequence tags (ESTs), for the human GABA_BR2 and GABA_BR1 genes. The human ESTs were identified using a search with the rat GABA_BR1 amino acid sequence as the query. The GABA_B 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 GABA_BR2, accession number T07621; human EST GABA_BR1, X90542; rat GABA_BR1, 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.)