GABA Receptor Function
Published by Anonymous on 2007/9/30 (3235 reads)
1: J Clin Psychiatry. 2005;66 Suppl 2:14-20.
The GABA-benzodiazepine receptor complex: structure, function, and role in anxiety.
Roy-Byrne PP.
Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA 98104, USA. roybyrne@u.washington.edu
Benzodiazepines bind to a specific site on the gamma-aminobutyric acid (GABA)-benzodiazepine receptor complex. This complex has been implicated in the pathophysiology of anxiety by numerous pre-clinical and clinical studies. Preclinical studies have shown that there are multiple molecular forms of this receptor complex, that these genetically coded variations are linked to specific actions of the benzodiazepines, and that receptors are located in neuroanatomical areas known to mediate the anxiety response in animals and humans. Human studies have shown that patients with pathologic anxiety have anomalous responses to drugs that specifically bind to these receptors and have reduced numbers of benzodiazepine receptors in key brain areas that regulate anxiety responses. More recent preclinical studies suggest that molecular alterations in this receptor complex may produce findings in animals similar to those observed in anxious humans. Finally, chronic treatment with benzodiazepines causes the development of tolerance, which may be associated with molecular changes and a pharmacologic response profile similar to that observed in pathologically anxious humans.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 15762815 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
2: Sci STKE. 2005 Feb 8;2005(270):pe5.
Alpha subunit position and GABA receptor function.
Burt DR.
Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201, USA. dburt@umaryland.edu
GABA(A) (gamma-aminobutyric acid type A) receptors are ligand-gated ion channels composed of five subunits, generally two alphas, two betas, and a gamma2. Recent research in which sets of subunits containing alpha1 or alpha6 subunits were artificially linked has revealed the importance of subunit position in determining GABA(A) receptor function. Sensitivity to benzodiazepines depended on juxtaposition of an alpha1 subunit with the gamma2 subunit, whereas sensitivity to furosemide depended only on the presence of an alpha6 subunit and not on its specific location. The major utility of the linked subunit approach is to provide a mechanism for discovering the functional signatures of defined subunit arrangements, and thus a route to identifying such arrangements in vivo.
Publication Types:
Review
PMID: 15701893 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
3: Biochem Pharmacol. 2004 Oct 15;68(8):1541-8.
GABA(B) receptor alterations as indicators of physiological and pharmacological function.
Enna SJ, Bowery NG.
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical School, 3901 Rainbow Boulevard, Mail Stop 1018, Kansas City, Kansas 66160-0227, USA. senna@kumc.edu
Given the widespread distribution of GABA(B) receptors throughout the central nervous system, and within certain peripheral organs, it is likely their selective pharmacological manipulation could be of benefit in the treatment of a variety of disorders. Studies aimed at defining the clinical potential of GABA(B) receptor agonists and antagonists have included gene deletion experiments, examination of changes in receptor binding, subunit expression and function in diseased tissue, as well as after the chronic administration of drugs. The results indicate that a functional GABA(B) receptor requires the combination of GABA(B(1)) and GABA(B(2)) subunits, that receptor function does not always correlate with subunit expression and receptor binding, and that GABA(B) receptor modifications may be associated with the clinical response to antidepressants, mood stabilizers, and GABA(B) receptor agonists and antagonists. Moreover, changes in GABA(B) binding or expression suggest this receptor may be involved in mediating symptoms associated with chronic pain, epilepsy and schizophrenia. This, together with results from other types of studies, indicates the potential therapeutic value of developing drugs capable of selectively activating, inhibiting, or modulating GABA(B) receptor function.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 15451397 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
4: Curr Opin Pharmacol. 2003 Feb;3(1):12-8.
GABA(A) receptor function and pharmacology in epilepsy and status epilepticus.
Jones-Davis DM, Macdonald RL.
University of Michigan, Ann Arbor, MI 48104-1687, USA.
GABA(A) (gamma-n-aminobutyric acid) receptor dysfunction has long been implicated in the development of epilepsy and status epilepticus. Recent advances have been made in understanding the cellular, pharmacological and genetic involvement of GABA(A) receptors in seizure disorders. In particular, genetic mutations found in GABA(A) receptor subunits strongly implicate the GABA(A) receptor in idiopathic generalised epilepsies.
Publication Types:
Review
PMID: 12550736 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
5: Curr Top Med Chem. 2002 Aug;2(8):795-816.
Subunit composition, distribution and function of GABA(A) receptor subtypes.
Sieghart W, Sperk G.
Section of Biochemical Psychiatry, University Clinic for Psychiatry, and Department of Biochemistry and Molecular Biology, Brain Research Institute, University of Vienna, Vienna, Austria. Werner.Sieghart@univie.ac.at
GABA(A) receptors are the major inhibitory neurotransmitter receptors in the brain and are the site of action of many clinically important drugs. These receptors are composed of five subunits that can belong to eight different subunit classes. Depending on their subunit composition, these receptors exhibit distinct pharmacological and electrophysiological properties. Recent studies on recombinant and native GABA(A) receptors suggest the existence of far more receptor subtypes than previously assumed. Thus, receptors composed of one, two, three, four, or five different subunits might exist in the brain. Studies on the regional, cellular and subcellular distribution of GABA(A) receptor subunits, and on the co-localization of these subunits at the light and electron microscopic level for the first time provide information on the distribution of GABA(A) receptor subtypes in the brain. These studies will have to be complemented by electrophysiological and pharmacological studies on the respective recombinant and native receptors to finally identify the receptor subtypes present in the brain. The distinct cellular and subcellular location of individual receptor subtypes suggests that they exhibit specific functions in the brain that can be selectively modulated by subtype specific drugs. This conclusion is supported by the recent demonstration that different GABA(A) receptor subtypes mediate different effects of benzodiazepines. Together, these results should cause a revival of GABA(A) receptor research and strongly stimulate the development of drugs with a higher selectivity for alpha2-, alpha3-, or alpha5-subunit-containing receptor subtypes. Such drugs might exhibit quite selective clinical effects.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 12171572 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
6: Trends Pharmacol Sci. 2000 Nov;21(11):411-3.
Unraveling the function of GABA(A) receptor subtypes.
Sieghart W.
Brain Research Institute of the University of Vienna, Division of Biochemistry and Molecular Biology, Austria. Werner.Sieghart@univie.ac.at
Publication Types:
Review
PMID: 11121567 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
7: Adv Neurol. 1999;79:499-510.
GABA receptor function and epilepsy.
Olsen RW, DeLorey TM, Gordey M, Kang MH.
Department of Molecular and Medical Pharmacology, UCLA School of Medicine 90095, USA.
Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 10514838 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
8: J Neurosci Res. 1995 May 1;41(1):1-7.
Modulatory actions of gamma aminobutyric acid (GABA) on GABA type A receptor subunit expression and function.
Schousboe A, Redburn DA.
Department of Biological Sciences, Royal Danish School of Pharmacy, Copenhagen.
Gamma aminobutyric acid (GABA) is present in the central nervous system (CNS) during very early embryogenesis. It is therefore likely to play a role not only as a neurotransmitter but also as a signal molecule for neuronal differentiation, growth, and development. It has been firmly established that formation of synapses is strengthened by GABA, and the expression of certain subunits of the GABA type A (GABAA) receptor complex is clearly promoted by GABA. This latter effect of GABA may have profound implications for the functional activity of GABAergic synapses since the pharmacological properties of GABAA receptors are governed by the subunit composition of the receptor complex. Dynamic changes in GABAA receptor expression and diversity during development and differentiation may therefore play important roles for the inhibitory potential of the CNS during mature stages.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 7674371 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
9: Tanpakushitsu Kakusan Koso. 1990 Jun;35(8):1455-64.
[Structure and function of GABA receptor in the brain]
[Article in Japanese]
Kuriyama K, Hirouchi M.
Department of Pharmacology, Kyoto Prefectural University of Medicine, Japan.
Publication Types:
Review
PMID: 1695758 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
10: Ann Med. 1990;22(4):241-6.
Alcohol and GABA-benzodiazepine receptor function.
Ticku MK.
University of Texas Health Science Center, San Antonio 78284-7764.
gamma-Aminobutyric acid (GABA)A is a major inhibitory neurotransmitter in the mammalian CNS. GABAA ergic synapse is also an important site of action for a variety of centrally acting drugs, including benzodiazepines and barbiturates. Several lines of electrophysiological, behavioral, and biochemical studies implicate GABAA ergic synapse in the actions of alcohol. In electrophysiological studies, alcohol has been reported to enhance GABA-mediated responses in cortical neurons, spinal cord and substantia nigra, albeit, negative results have also been reported. In behavioral studies, GABAmimetics enhance alcohol's effects on motor coordination, while GABA antagonists have the opposite effect. In drug-combination studies, subeffective doses of alcohol, in combination with subeffective doses of other GABAmimetics, potentiate each other's effect in several seizure models. In functional studies, alcohol has been reported to potentiate GABA receptor-mediated 36Cl-flux in microsacs, neurosynaptosomes, and cultured spinal cord neurons at pharmacologically relevant concentrations. The potentiating effect of alcohol is blocked by GABA antagonists and the inverse agonists of the benzodiazepine receptor site. Taken together, these studies indicate that some of the central effects of alcohol are mediated via facilitation of GABAAergic transmission.
Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 1701092 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
11: Nippon Yakurigaku Zasshi. 1989 Jul;94(1):7-15.
[Structure and function of gamma-aminobutyric acid (GABA) receptor: current state and prospectives]
[Article in Japanese]
Kuriyama K, Hirouchi M.
Department of Pharmacology, Kyoto Prefectural University of Medicine, Japan.
The gamma-aminobutyric acid (GABA) receptor has been classified into two receptor subtypes (GABAA and GABAB receptors) based on their pharmacological properties. The GABAA receptor in the central nervous system (CNS) has been found to be coupled structurally as well as functionally with the benzodiazepine receptor and Cl- channel. Purified GABAA receptor from bovine brain consisted of both alpha and beta subunits. The complementary DNAs encoding the GABAA receptor alpha and beta subunits have been cloned; and from their elucidated nucleotide sequences, the amino acid sequences of the subunits were deduced. The structure of both subunits, having four putative membrane domains, has been found to be similar to other ligand-gated receptors such as the nicotinic acetylcholine receptor alpha subunit and glycine receptor 48K subunit. Therefore, it has been suggested that these ligand-gated receptors comprise a superfamily. In addition, the presence of similarities in the nucleotide and deduced amino acid sequences of human brain GABAA receptor with those of bovine brain has been noted. On the other hand, the GABAB receptor, which is insensitive to bicuculline but sensitive to baclofen, has been found to be pharmacologically distinct from the GABAA receptor. The GABAB receptor in the brain has been found to be coupled with GTP-binding protein and generates the inhibitory transmission coupled with various intracellular effector systems such as adenylate cyclase and phosphoinositides turnover. The exact structure and function of the GABAB receptor in the CNS, however, remain to be clarified in future studies.
Publication Types:
English Abstract
Review
PMID: 2551802 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
12: Life Sci. 1986 Nov 24;39(21):1969-76.
Barbiturate and benzodiazepine modulation of GABA receptor binding and function.
Olsen RW, Yang J, King RG, Dilber A, Stauber GB, Ransom RW.
The inhibitory neurotransmitter gamma-aminobutyric acid (GABA) acts primarily on receptors that increase chloride permeability in postsynaptic neurons. These receptors are defined by sensitivity to the agonist muscimol and the antagonist bicuculline, and are also subject to indirect allosteric inhibition by picrotoxin-like convulsants and enhancement by the clinically important drugs, the benzodiazepines and the barbiturates. All of these drugs modulate GABA-receptor regulated chloride channels at the cellular level assayed by electrophysiological or radioactive ion tracer techniques. Specific receptor sites for GABA, benzodiazepines, picrotoxin/convulsants, and barbiturates can be assayed in vitro by radioactive ligand binding. Mutual chloride-dependent allosteric interactions between the four receptor sites indicate that they are all coupled in the same membrane macromolecular complex. Indirect effects of barbiturates on the other three binding sites define a pharmacologically specific, stereospecific receptor. All of the activities can be solubilized in the mild detergent 3-[(3-cholamidopropyl)-dimethylammonio]propane sulfonate (CHAPS) and co-purify as a single protein complex.
Publication Types:
Comparative Study
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 2431244 [PubMed - indexed for MEDLINE]
The GABA-benzodiazepine receptor complex: structure, function, and role in anxiety.
Roy-Byrne PP.
Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA 98104, USA. roybyrne@u.washington.edu
Benzodiazepines bind to a specific site on the gamma-aminobutyric acid (GABA)-benzodiazepine receptor complex. This complex has been implicated in the pathophysiology of anxiety by numerous pre-clinical and clinical studies. Preclinical studies have shown that there are multiple molecular forms of this receptor complex, that these genetically coded variations are linked to specific actions of the benzodiazepines, and that receptors are located in neuroanatomical areas known to mediate the anxiety response in animals and humans. Human studies have shown that patients with pathologic anxiety have anomalous responses to drugs that specifically bind to these receptors and have reduced numbers of benzodiazepine receptors in key brain areas that regulate anxiety responses. More recent preclinical studies suggest that molecular alterations in this receptor complex may produce findings in animals similar to those observed in anxious humans. Finally, chronic treatment with benzodiazepines causes the development of tolerance, which may be associated with molecular changes and a pharmacologic response profile similar to that observed in pathologically anxious humans.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 15762815 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
2: Sci STKE. 2005 Feb 8;2005(270):pe5.
Alpha subunit position and GABA receptor function.
Burt DR.
Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201, USA. dburt@umaryland.edu
GABA(A) (gamma-aminobutyric acid type A) receptors are ligand-gated ion channels composed of five subunits, generally two alphas, two betas, and a gamma2. Recent research in which sets of subunits containing alpha1 or alpha6 subunits were artificially linked has revealed the importance of subunit position in determining GABA(A) receptor function. Sensitivity to benzodiazepines depended on juxtaposition of an alpha1 subunit with the gamma2 subunit, whereas sensitivity to furosemide depended only on the presence of an alpha6 subunit and not on its specific location. The major utility of the linked subunit approach is to provide a mechanism for discovering the functional signatures of defined subunit arrangements, and thus a route to identifying such arrangements in vivo.
Publication Types:
Review
PMID: 15701893 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
3: Biochem Pharmacol. 2004 Oct 15;68(8):1541-8.
GABA(B) receptor alterations as indicators of physiological and pharmacological function.
Enna SJ, Bowery NG.
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical School, 3901 Rainbow Boulevard, Mail Stop 1018, Kansas City, Kansas 66160-0227, USA. senna@kumc.edu
Given the widespread distribution of GABA(B) receptors throughout the central nervous system, and within certain peripheral organs, it is likely their selective pharmacological manipulation could be of benefit in the treatment of a variety of disorders. Studies aimed at defining the clinical potential of GABA(B) receptor agonists and antagonists have included gene deletion experiments, examination of changes in receptor binding, subunit expression and function in diseased tissue, as well as after the chronic administration of drugs. The results indicate that a functional GABA(B) receptor requires the combination of GABA(B(1)) and GABA(B(2)) subunits, that receptor function does not always correlate with subunit expression and receptor binding, and that GABA(B) receptor modifications may be associated with the clinical response to antidepressants, mood stabilizers, and GABA(B) receptor agonists and antagonists. Moreover, changes in GABA(B) binding or expression suggest this receptor may be involved in mediating symptoms associated with chronic pain, epilepsy and schizophrenia. This, together with results from other types of studies, indicates the potential therapeutic value of developing drugs capable of selectively activating, inhibiting, or modulating GABA(B) receptor function.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 15451397 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
4: Curr Opin Pharmacol. 2003 Feb;3(1):12-8.
GABA(A) receptor function and pharmacology in epilepsy and status epilepticus.
Jones-Davis DM, Macdonald RL.
University of Michigan, Ann Arbor, MI 48104-1687, USA.
GABA(A) (gamma-n-aminobutyric acid) receptor dysfunction has long been implicated in the development of epilepsy and status epilepticus. Recent advances have been made in understanding the cellular, pharmacological and genetic involvement of GABA(A) receptors in seizure disorders. In particular, genetic mutations found in GABA(A) receptor subunits strongly implicate the GABA(A) receptor in idiopathic generalised epilepsies.
Publication Types:
Review
PMID: 12550736 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
5: Curr Top Med Chem. 2002 Aug;2(8):795-816.
Subunit composition, distribution and function of GABA(A) receptor subtypes.
Sieghart W, Sperk G.
Section of Biochemical Psychiatry, University Clinic for Psychiatry, and Department of Biochemistry and Molecular Biology, Brain Research Institute, University of Vienna, Vienna, Austria. Werner.Sieghart@univie.ac.at
GABA(A) receptors are the major inhibitory neurotransmitter receptors in the brain and are the site of action of many clinically important drugs. These receptors are composed of five subunits that can belong to eight different subunit classes. Depending on their subunit composition, these receptors exhibit distinct pharmacological and electrophysiological properties. Recent studies on recombinant and native GABA(A) receptors suggest the existence of far more receptor subtypes than previously assumed. Thus, receptors composed of one, two, three, four, or five different subunits might exist in the brain. Studies on the regional, cellular and subcellular distribution of GABA(A) receptor subunits, and on the co-localization of these subunits at the light and electron microscopic level for the first time provide information on the distribution of GABA(A) receptor subtypes in the brain. These studies will have to be complemented by electrophysiological and pharmacological studies on the respective recombinant and native receptors to finally identify the receptor subtypes present in the brain. The distinct cellular and subcellular location of individual receptor subtypes suggests that they exhibit specific functions in the brain that can be selectively modulated by subtype specific drugs. This conclusion is supported by the recent demonstration that different GABA(A) receptor subtypes mediate different effects of benzodiazepines. Together, these results should cause a revival of GABA(A) receptor research and strongly stimulate the development of drugs with a higher selectivity for alpha2-, alpha3-, or alpha5-subunit-containing receptor subtypes. Such drugs might exhibit quite selective clinical effects.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 12171572 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
6: Trends Pharmacol Sci. 2000 Nov;21(11):411-3.
Unraveling the function of GABA(A) receptor subtypes.
Sieghart W.
Brain Research Institute of the University of Vienna, Division of Biochemistry and Molecular Biology, Austria. Werner.Sieghart@univie.ac.at
Publication Types:
Review
PMID: 11121567 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
7: Adv Neurol. 1999;79:499-510.
GABA receptor function and epilepsy.
Olsen RW, DeLorey TM, Gordey M, Kang MH.
Department of Molecular and Medical Pharmacology, UCLA School of Medicine 90095, USA.
Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 10514838 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
8: J Neurosci Res. 1995 May 1;41(1):1-7.
Modulatory actions of gamma aminobutyric acid (GABA) on GABA type A receptor subunit expression and function.
Schousboe A, Redburn DA.
Department of Biological Sciences, Royal Danish School of Pharmacy, Copenhagen.
Gamma aminobutyric acid (GABA) is present in the central nervous system (CNS) during very early embryogenesis. It is therefore likely to play a role not only as a neurotransmitter but also as a signal molecule for neuronal differentiation, growth, and development. It has been firmly established that formation of synapses is strengthened by GABA, and the expression of certain subunits of the GABA type A (GABAA) receptor complex is clearly promoted by GABA. This latter effect of GABA may have profound implications for the functional activity of GABAergic synapses since the pharmacological properties of GABAA receptors are governed by the subunit composition of the receptor complex. Dynamic changes in GABAA receptor expression and diversity during development and differentiation may therefore play important roles for the inhibitory potential of the CNS during mature stages.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 7674371 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
9: Tanpakushitsu Kakusan Koso. 1990 Jun;35(8):1455-64.
[Structure and function of GABA receptor in the brain]
[Article in Japanese]
Kuriyama K, Hirouchi M.
Department of Pharmacology, Kyoto Prefectural University of Medicine, Japan.
Publication Types:
Review
PMID: 1695758 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
10: Ann Med. 1990;22(4):241-6.
Alcohol and GABA-benzodiazepine receptor function.
Ticku MK.
University of Texas Health Science Center, San Antonio 78284-7764.
gamma-Aminobutyric acid (GABA)A is a major inhibitory neurotransmitter in the mammalian CNS. GABAA ergic synapse is also an important site of action for a variety of centrally acting drugs, including benzodiazepines and barbiturates. Several lines of electrophysiological, behavioral, and biochemical studies implicate GABAA ergic synapse in the actions of alcohol. In electrophysiological studies, alcohol has been reported to enhance GABA-mediated responses in cortical neurons, spinal cord and substantia nigra, albeit, negative results have also been reported. In behavioral studies, GABAmimetics enhance alcohol's effects on motor coordination, while GABA antagonists have the opposite effect. In drug-combination studies, subeffective doses of alcohol, in combination with subeffective doses of other GABAmimetics, potentiate each other's effect in several seizure models. In functional studies, alcohol has been reported to potentiate GABA receptor-mediated 36Cl-flux in microsacs, neurosynaptosomes, and cultured spinal cord neurons at pharmacologically relevant concentrations. The potentiating effect of alcohol is blocked by GABA antagonists and the inverse agonists of the benzodiazepine receptor site. Taken together, these studies indicate that some of the central effects of alcohol are mediated via facilitation of GABAAergic transmission.
Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 1701092 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
11: Nippon Yakurigaku Zasshi. 1989 Jul;94(1):7-15.
[Structure and function of gamma-aminobutyric acid (GABA) receptor: current state and prospectives]
[Article in Japanese]
Kuriyama K, Hirouchi M.
Department of Pharmacology, Kyoto Prefectural University of Medicine, Japan.
The gamma-aminobutyric acid (GABA) receptor has been classified into two receptor subtypes (GABAA and GABAB receptors) based on their pharmacological properties. The GABAA receptor in the central nervous system (CNS) has been found to be coupled structurally as well as functionally with the benzodiazepine receptor and Cl- channel. Purified GABAA receptor from bovine brain consisted of both alpha and beta subunits. The complementary DNAs encoding the GABAA receptor alpha and beta subunits have been cloned; and from their elucidated nucleotide sequences, the amino acid sequences of the subunits were deduced. The structure of both subunits, having four putative membrane domains, has been found to be similar to other ligand-gated receptors such as the nicotinic acetylcholine receptor alpha subunit and glycine receptor 48K subunit. Therefore, it has been suggested that these ligand-gated receptors comprise a superfamily. In addition, the presence of similarities in the nucleotide and deduced amino acid sequences of human brain GABAA receptor with those of bovine brain has been noted. On the other hand, the GABAB receptor, which is insensitive to bicuculline but sensitive to baclofen, has been found to be pharmacologically distinct from the GABAA receptor. The GABAB receptor in the brain has been found to be coupled with GTP-binding protein and generates the inhibitory transmission coupled with various intracellular effector systems such as adenylate cyclase and phosphoinositides turnover. The exact structure and function of the GABAB receptor in the CNS, however, remain to be clarified in future studies.
Publication Types:
English Abstract
Review
PMID: 2551802 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
12: Life Sci. 1986 Nov 24;39(21):1969-76.
Barbiturate and benzodiazepine modulation of GABA receptor binding and function.
Olsen RW, Yang J, King RG, Dilber A, Stauber GB, Ransom RW.
The inhibitory neurotransmitter gamma-aminobutyric acid (GABA) acts primarily on receptors that increase chloride permeability in postsynaptic neurons. These receptors are defined by sensitivity to the agonist muscimol and the antagonist bicuculline, and are also subject to indirect allosteric inhibition by picrotoxin-like convulsants and enhancement by the clinically important drugs, the benzodiazepines and the barbiturates. All of these drugs modulate GABA-receptor regulated chloride channels at the cellular level assayed by electrophysiological or radioactive ion tracer techniques. Specific receptor sites for GABA, benzodiazepines, picrotoxin/convulsants, and barbiturates can be assayed in vitro by radioactive ligand binding. Mutual chloride-dependent allosteric interactions between the four receptor sites indicate that they are all coupled in the same membrane macromolecular complex. Indirect effects of barbiturates on the other three binding sites define a pharmacologically specific, stereospecific receptor. All of the activities can be solubilized in the mild detergent 3-[(3-cholamidopropyl)-dimethylammonio]propane sulfonate (CHAPS) and co-purify as a single protein complex.
Publication Types:
Comparative Study
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 2431244 [PubMed - indexed for MEDLINE]
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