ABSTRACT
GABA(C) receptors mediate rapid inhibitory neurotransmission in retina. We have mapped, in detail, the human genes which encode the three polypeptides that comprise this receptor: rho1 (GABRR1), rho2 (GABRR2) and rho3 (GABRR3). We show that GABRR1 and GABRR2 are located close together, in a region of chromosome 6q that contains loci for inherited disorders of the eye, but that GABRR3 maps to chromosome 3q11-q13.3. Our mapping data suggest that the rho polypeptide genes, which are thought to share a common ancestor with GABA(A) receptor subunit genes, diverged at an early stage in the evolution of this gene family.
Subject(s)
Chromosomes, Human, Pair 3 , Receptors, GABA-B , Receptors, GABA/genetics , Amino Acid Sequence , Base Sequence , Chromosome Mapping , Genetic Linkage , Humans , Molecular Sequence Data , Receptors, GABA-ASubject(s)
Multigene Family , Receptors, GABA-A/genetics , Base Sequence , Chromosome Mapping , Chromosomes, Human, Pair 4/genetics , Chromosomes, Human, Pair 5/genetics , DNA Primers/genetics , Evolution, Molecular , Genetic Linkage , Genetic Markers , Humans , Protein Conformation , Receptors, GABA-A/chemistryABSTRACT
OBJECTIVE: gamma-Aminobutyric acid type A (GABAA) receptor subunit genes are candidate genes for panic disorder. Benzodiazepine agonists acting at this receptor can suppress panic attacks, and both inverse agonists and antagonists can precipitate them. The human GABAA receptor subtypes are composed of various combinations of 13 subunits, each encoded by a unique gene. The authors tested eight of these subunits in a candidate gene linkage study of panic disorder. METHOD: In 21 U.S. and five Icelandic multiplex pedigrees of panic disorder, 104 individuals had DSM-III-R panic disorder (the narrowly defined affected phenotype) and 134 had either this diagnosis or subsyndromal panic disorder characterized by panic attacks that failed to meet either the criterion of attack frequency or the number of criterion symptoms necessary for a definite diagnosis (the broadly defined affected phenotype). The authors conducted lod score linkage analyses with both phenotypes using both a dominant and a recessive model of inheritance for the following loci: GABRA1-GABRA5 (alpha 1-alpha 5), GABRB1 (beta 1), GABRB3 (beta 3), and GABRG2 (gamma 2). RESULTS: The results failed to support the hypothesis that any of these genes cause panic disorder in a majority of the pedigrees. CONCLUSIONS: Within the limitations of the candidate gene linkage method, panic disorder does not appear to be caused by mutation in any of the eight GABAA receptor genes tested.
Subject(s)
Panic Disorder/genetics , Receptors, GABA-A/genetics , Adult , Agoraphobia/genetics , Female , Genetic Heterogeneity , Genetic Linkage , Genetic Variation , Humans , Lod Score , Male , Middle Aged , Models, Genetic , Mutation , Panic Disorder/diagnosis , Pedigree , Phenotype , Polymorphism, GeneticABSTRACT
The pharmacological properties of homo-oligomeric channels formed by the GABA type A receptor-like rho1 and rho2 polypeptides are very reminiscent of those of the GABA type C receptors that have been extensively characterized in the retina. Similar receptors have been reported to occur in certain brain regions of a variety of vertebrate species. We have used in situ hybridization to investigate the expression patterns of the rho1- and rho2-polypeptide genes in the brain of the 1-day-old chick (Gallus domesticus) and the adult rat (Rattus norvegicus). Our results show that in the chick both the rho1- and rho2-subunit transcripts are present in the cerebellum, the optic tectum, the epithalamus and the nucleus pretectalis. However, the two messenger RNAs are often found in different populations of cells. Thus, only the rho1-subunit gene is expressed in the deep cerebellar nuclei, the dorsal thalamus, the ectostriatum and the tractus vestibulomesencephalicus, while only the rho2-subunit gene is transcribed in the nucleus habenularis lateralis and the nucleus isthmo-opticus. In contrast, neither of the rho-polypeptide messenger RNAs can be detected by in situ hybridization in the rat central nervous system. Reverse transcription-polymerase chain reaction amplification has been used to confirm the expression of the two rho-subunit genes in the chicken brain. Surprisingly, this highly sensitive technique also revealed transcription of these genes in the rat brain. We conclude that the rho1- and rho2-subunit genes are expressed at a much higher level in the avian brain than in the rat brain and that, at least in birds, subtypes of the GABA(C) receptor exist.
Subject(s)
Brain Chemistry/physiology , Chickens/metabolism , Receptors, GABA/biosynthesis , Animals , Brain/cytology , Brain/growth & development , Brain Chemistry/genetics , In Situ Hybridization , Oligonucleotide Probes , Polymerase Chain Reaction , RNA, Messenger/biosynthesis , Rats , Receptors, GABA/genetics , Species SpecificityABSTRACT
We have amplified partial complementary DNAs for the chicken gamma-aminobutyric acid type C (GABAC) receptor rho 1 and rho 2 subunits using the polymerase chain reaction. These nucleotide sequences have been utilized to design specific oligonucleotide probes for the in situ hybridization localization of the corresponding messenger RNAs (mRNAs) in the 1-day-old chick retina. Although both transcripts are found almost exclusively in the inner nuclear layer, their distributions differ markedly. From the locations of the hybridization signals, we deduce that the rho 1-subunit mRNA is present mainly in bipolar cells and that the rho 2-subunit mRNA is present in both amacrine and horizontal cells. These results suggest that the rho 1 and rho 2 subunits frequently occur in different receptor complexes and, therefore, that subtypes of the GABAC receptor exist.
