Biochemical Properties of the GABA/Barbiturate/Benzodiazepine Receptor-Chloride Ion Channel Complex

Olsen, Richard W.; Wong, Erik H. F.; Stauber, G. B.; Murakami, Dean M.; King, R. G.; Fischer, James B.

doi:10.1007/978-1-4684-4805-4_17

Cited by 17 publications

(8 citation statements)

References 29 publications

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“…Mamalaki & Barnard, 1983;Olsen, Wong, Stauber, Murakami, King & Fischer, 1984) are formed by hetero-oligomers of subunits with molecular weights of about 50 kDa. The size of these subunits is much larger than would be required to form five membrane-spanning a-helices.…”

Section: Comparison With Post-8ynaptic Channels In Inhibitory Synapsesmentioning

confidence: 99%

Mechanism of anion permeation through channels gated by glycine and gamma‐aminobutyric acid in mouse cultured spinal neurones.

Bormann

Hamill

Sakmann

1987

The Journal of Physiology

1,132

113

738

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SUMMARY1. The ion-selective and ion transport properties of glycine receptor (GlyR) and y-aminobutyric acid receptor (GABAR) channels in the soma membrane of mouse spinal cord neurones were investigated using the whole-cell, cell-attached and outside-out patch versions of the patch-clamp technique.2. Current-voltage (I-V) relations oftransmitter-activated currents obtained from whole-cell measurements with 145 mM-Cl-intracellularly and extracellularly, showed outward rectification. In voltage-jump experiments, the instantaneous I-V relations were linear, and the steady-state I-V relations were rectifying outwardly indicating that the gating of GlyR and GABAR channels is voltage sensitive.3. The reversal potential of whole-cell currents shifted 56 mV per tenfold change in internal Cl-activity indicating activation of Cl--selective channels. The permeability ratio of K+ to Cl-(PK/PC1) was smaller than 0 05 for both channels.4. The permeability sequence for large polyatomic anions was formate > bicarbonate > acetate > phosphate > propionate for GABAR channels; phosphate and propionate were not measurably permeant in GlyR channels. This indicates that open GlyR and GABAR channels have effective pore diameters of 5-2 and 5-6 A, respectively. The sequence of relative permeabilities for small anions was SCN-> 1-> Br-> Cl-> F-for both channels.5. GlyR and GABAR channels are multi-conductance-state channels. In cellattached patches the single-channel slope conductances close to 0 mV membrane potential were 29, 18 and 10 pS for glycine, and 28, 17 and 10 pS for GABA-activated channels. The most frequently observed (main) J. BORMANN, 0. P. HAMILL AND B. SAKMANN I-> SCN-> F-for both channels. This is nearly the inverse sequence of that found for the permeability of these ions indicating the presence of binding sites for ions in the channel.8. The conductance-activity relation of GlyR and GABAR channels for Cl-was described by hyperbolic curves. The maximal conductances (Ymax) were 92 and 72 pS; the half-saturation activities (Ki) were 108 and 155 mM-Cl-for GlyR and GABAR channels, respectively. 9. The conductance-activity relation for SCN-was characterized by maximal conductances of 35 pS (GlyR) and 32 pS (GABAR). The half-saturation activities were 46 and 57 mm, respectively. In equal mixtures of SCN-and Cl-on both membrane sides the channel conductance showed anomalous mole-fraction dependence. This indicates that the channels contain at least two binding sites for anions.10. The difference between GlyR and GABAR channels in their main-state Clconductance could be caused by a small energy difference (-1 kJ mol-1) in the interaction of Cl-ions with the channel wall. The observation that both GlyR and GABAR channels display comparable conductance states, show similar permeability and conductance sequences for small anions, a similar conductance saturation curve for Cl-and SCN-and similar mole-fraction dependence of their conductance in Cl--SCN-mixtures could indicate that both receptor channels have a similar molecular st...

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Section: Comparison With Post-8ynaptic Channels In Inhibitory Synapsesmentioning

confidence: 99%

Mechanism of anion permeation through channels gated by glycine and gamma‐aminobutyric acid in mouse cultured spinal neurones.

Bormann

Hamill

Sakmann

1987

The Journal of Physiology

1,132

113

738

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“…33 Diazepam works directly on the benzodiazepine receptor, which is located on the GABA receptor complex, to open the chloride channel. 35 Muscimol is a GABA A agonist but is thought to have some toxic effects. 36 Baclofen is a selective GABA B receptor agonist.…”

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confidence: 99%

Role for gamma-aminobutyric acid in selective vulnerability in gerbils.

Sternau

Lust

Ricci

et al. 1989

Stroke

172

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We tested the efficacy of various putative neuroprotective agents in the gerbil model of delayed neuronal death. The selective loss of anterior CA1 neurons of the hippocampus 4 days after 5 minutes of bilateral ischemia was complete in >90% of the gerbils examined. We tested 11 agents for their ability to protect against neuronal loss. Only those agents that were associated with the GABAergic system exhibited protection and only when administered before the ischemic insult. The possibility that delayed neuronal death is the result of a primary defect in inhibitory neurotransmission is considered. (Stroke 1989;20:281-287) S elective vulnerability (SV) of hippocampal neurons was first reported more than 100 years ago, 1 and the mechanism for this phenomenon has yet to be elucidated. Many hypotheses have been proposed to explain the delayed neuronal death (DND) that occurs in the CA1 pyramidal cells following an ischemic event.2 -10 A more recent hypothesis proposes that certain excitatory amino acids (i.e., glutamate and aspartate) may act as endogenous neurotoxins following seizures, ischemia, and hypoglycemia." While extracellular glutamate in low concentrations is toxic to selected neuronal populations, 12 it is still unclear whether glutamate antagonists can prevent DND. 13MFurther support of the excitotoxic hypothesis was provided by Rothman, 15 who reported that hippocampal neuronal cultures could be protected from anoxic damage by blocking synaptic activity. These results, along with the demonstration that deafferentation of the Schaeffer collaterals blocked postischemic CA1 neuronal death, suggest that synaptic transduction is an important component of SV. 1617While glutamate may be the toxin, the primary insult that gives rise to glutamate toxicity does not necessarily have to be intrinsic to this system. We questioned whether the insult is an exaggerated excitation secondary to an inhibitory defect within the hippocampus. The major inhibitory pathway

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“…-Aminobutyric acid (GABA), the main inhibitory neurotransmitter in the vertebrate central nervous system, counteracts the pathologic as well as the physiologic eOE ects of excitatory amino acids (Roberts 1974). The majority of inhibitory eOE ects of GABA are mediated through activation of GABA A receptors, resulting in chloride channel opening and subsequent membrane hyperpolarization (Olsen et al 1984). Benzodiazepines such as diazepam potentiate GABA A neurotransmission.…”

Section: Introductionmentioning

confidence: 99%

Diazepam does not reduce infarct size in rats subjected to transient occlusion of the middle cerebral artery when normothermia is maintained

Kuhmonen

Lukkarinen

Gröhn

et al. 2002

Journal of Pharmacy and Pharmacology

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Activation of the gamma-amino butyric acid (GABA)-ergic system might protect against the damage that occurs after cerebral ischaemia. We examined this hypothesis by administering diazepam to rats subjected to transient middle cerebral artery occlusion (MCAO) using the intraluminal thread method. Diffusion MRI (DWI) and perfusion imaging (PI) were acquired during MCAO to assess brain tissue status and haemodynamics, respectively. Rats were intraperitoneally injected with either 10 mg kg(-1) diazepam (n = 5) or vehicle (n = 5) both 30 min and 90 min after the onset of MCAO. To exclude the possibility that neuroprotection was due to the hypothermic action of the drug, body temperature was maintained at 37-38 degrees C for up to 7 h postischaemia with a feed-back controlled thermoregulatory unit. Infarct volumes quantified 2 days after MCAO from T(2)-weighted images were similar in ischaemic control rats and in ischaemic rats treated with diazepam. We conclude that diazepam-induced enhancement of GABA(A) activity does not effectively protect against neuronal damage that occurs after transient MCAO in normothermic rats.

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Biochemical Properties of the GABA/Barbiturate/Benzodiazepine Receptor-Chloride Ion Channel Complex

Cited by 17 publications

References 29 publications

Mechanism of anion permeation through channels gated by glycine and gamma‐aminobutyric acid in mouse cultured spinal neurones.

Mechanism of anion permeation through channels gated by glycine and gamma‐aminobutyric acid in mouse cultured spinal neurones.

Role for gamma-aminobutyric acid in selective vulnerability in gerbils.

Diazepam does not reduce infarct size in rats subjected to transient occlusion of the middle cerebral artery when normothermia is maintained

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