Agonist‐Dependent Internalization of γ‐Aminobutyric Acid<sub>A</sub>/Benzodiazepine Receptors in Chick Cortical Neurons

Tehrani, Mohammad H. Jalilian; Barnes, Eugene M.

doi:10.1111/j.1471-4159.1991.tb08295.x

Cited by 61 publications

(47 citation statements)

References 11 publications

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“…Studies in which the organotypic cultures were exposed to either excessive extracellular GABA concentration with GABA uptake blocked or to the high affinity GABAR agonist muscimol also demonstrated that modulation of the surface expression of the ␥2 subunit was not dependent on direct ligand binding of the receptor. Although previous studies have demonstrated a ligand-dependent mechanism for the regulation of the surface expression of GABARs, these studies (Tehrani and Barnes, 1991;Calkin and Barnes, 1994) used longer incubation periods and higher concentrations of GABA than that used in the present study.…”

Section: Subunit-specific Trafficking Of Gabarsmentioning

confidence: 76%

“…Although reduced, this decrease did not reach statistical significance ( p ϭ 0.08, t test). A reduction in the surface expression of a subset of GABARs during SE could occur in response to either a ligand-independent mechanism (Stelzer and Shi, 1994;Chen and Wong, 1995;Lu et al, 2000) or a ligand-dependent mechanism (Tehrani and Barnes, 1991;Calkin and Barnes, 1994). The finding that NMDA was, at a minimum, necessary to induce a reduction in the surface expression of the ␥2 subunit in the organotypic culture is consistent with a ligand-independent mechanism.…”

Section: Changes In the Surface Expression Of Gabars Are Independent mentioning

confidence: 99%

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Subunit-Specific Trafficking of GABA_AReceptors during Status Epilepticus

Goodkin¹,

Joshi²,

et al. 2008

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It is proposed that a reduced surface expression of GABA A receptors (GABARs) contributes to the pathogenesis of status epilepticus (SE), a condition characterized by prolonged seizures. This hypothesis was based on the finding that prolonged epileptiform bursting (repetitive bursts of prolonged depolarizations with superimposed action potentials) in cultures of dissociated hippocampal pyramidal neurons (dissociated cultures) results in the increased intracellular accumulation of GABARs. However, it is not known whether this rapid modification in the surface-expressed GABAR pool results from selective, subunit-dependent or nonselective, subunit-independent internalization of GABARs. In hippocampal slices obtained from animals undergoing prolonged SE (SE-treated slices), we found that the surface expression of the GABAR ␤2/3 and ␥2 subunits was reduced, whereas that of the ␦ subunit was not. Complementary electrophysiological recordings from dentate granule cells in SE-treated slices demonstrated a reduction in GABAR-mediated synaptic inhibition, but not tonic inhibition. A reduction in the surface expression of the ␥2 subunit, but not the ␦ subunit was also observed in dissociated cultures and organotypic hippocampal slice cultures when incubated in an elevated KCl external medium or an elevated KCl external medium supplemented with NMDA, respectively. Additional studies demonstrated that the reduction in the surface expression of the ␥2 subunit was independent of direct ligand binding of the GABAR. These findings demonstrate that the regulation of surface-expressed GABAR pool during SE is subunit-specific and occurs independent of ligand binding. The differential modulation of the surface expression of GABARs during SE has potential implications for the treatment of this neurological emergency.

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Section: Subunit-specific Trafficking Of Gabarsmentioning

confidence: 76%

Section: Changes In the Surface Expression Of Gabars Are Independent mentioning

confidence: 99%

Subunit-Specific Trafficking of GABA_AReceptors during Status Epilepticus

Goodkin¹,

Joshi²,

et al. 2008

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“…Furthermore, we have shown that a peptide corresponding to the AP2 dileucine motif region of the receptor ␤ 2 subunit increases GABA-gated chloride currents in HEK 293 cells expressing recombinant receptors and also in cerebral cortical neurons. The observations that GABA A receptor cell surface expression is rapidly decreased following GABA A receptor stimulation (29), ischemia (30), and exposure of neurons to brain-derived neurotrophic factor (31) underscore the importance of understanding the mechanisms that regulate GABA A receptor endocytosis.…”

Section: Discussionmentioning

confidence: 99%

Constitutive GABAA Receptor Endocytosis Is Dynamin-mediated and Dependent on a Dileucine AP2 Adaptin-binding Motif within the β2 Subunit of the Receptor

Herring

Huang

Singh

et al. 2003

Journal of Biological Chemistry

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Receptor endocytosis is an important mechanism for regulating the synaptic efficacy of neurotransmitters. There is strong evidence that GABA A receptor endocytosis is clathrin-dependent; however, this process is not well understood. Here we demonstrate that in HEK 293 cells, endocytosis of GABA A receptors composed of either ␣ 1 ␤ 2 ␥ 2 L or ␣ 1 ␤ 2 subunits is blocked by the dominant negative dynamin construct K44A. Furthermore, we identify a dileucine AP2 adaptin-binding motif within the receptor ␤ 2 subunit that is critical for endocytosis. Internalization of GABA A receptors lacking this motif is dramatically inhibited, and the receptors appear to accumulate on the cell surface. Patch clamp analysis of receptors lacking the dileucine motif show that there is an increase in the peak amplitude of GABA-gated chloride currents compared with wild-type receptors. Additionally, GABA-gated chloride currents in HEK 293 cells expressing wild-type receptors are increased by introduction of a peptide corresponding to the dileucine motif region of the receptor ␤ 2 subunit but not by a control peptide containing alanine substitutions for the dileucine motif. In mouse brain cerebral cortical neurons, the dileucine motif peptide increases GABA-gated chloride currents of native GABA A receptors. This is the first report to our knowledge that an AP2 adaptin dileucine recognition motif is critical for the endocytosis of ligand-gated ion channels belonging to this superfamily.The GABA A receptor is a ligand-gated chloride channel that, upon activation by GABA 1 (␥-aminobutyric acid), mediates increases in chloride conductance resulting in membrane hyperpolarization and neuronal inhibition (1). The role of these receptors in hyperexcitability states, such as epilepsy and anxiety, is widely recognized. Importantly, GABA A receptors mediate the effects of benzodiazepines and barbiturates, two frequently prescribed classes of therapeutic agents. The GABA A receptor is a pentameric receptor composed of multiple subunits, each containing four membrane-spanning regions (M1-M4) with a large intracellular loop between M3 and M4. A number of subunits exist (␣ 1Ϫ6 , ␤ 1Ϫ3 , ␥ 1Ϫ3 , ␦, , ⑀, ), and receptors composed of ␣ 1 ␤ 2 ␥ 2 L subunits are believed to represent the predominant GABA A receptor subtype in the brain (1).Receptor endocytosis is known to regulate the cell surface expression of neurotransmitter receptors, and such regulation is an important mechanism for controlling the synaptic efficacy of neurotransmitters (2). Although GABA A receptors undergo endocytosis, the mechanism is not well understood. Several lines of evidence indicate that GABA A receptor endocytosis may be clathrin/dynamin-dependent. These include the presence of GABA A receptors in clathrin-coated vesicles isolated from brain (3), the colocalization of the receptor with transferrin receptors (4), and the colocalization and co-immunoprecipitation of hippocampal GABA A receptors with the clathrin adaptor complex AP2 adaptin (5). Additionally, peptides that dis...

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“…Some of these changes include internalization of the receptor, a subsensitivity to GABA, an uncoupling of sites at the GABA receptor complex (Wilson & Gallager, 1988;Roca et al, 1989;Tehrani & Barnes, 1991). Other mechanisms that might be involved are alterations in levels of GABA receptor subunit mRNA and receptor phosphorylation (Kang & Miller, 1991;Gyenes et al, 1994;Wu et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

Rate of change of blood concentrations is a major determinant of the pharmacodynamics of midazolam in rats

Cleton

Mazee

Voskuyl³

et al. 1999

British J Pharmacology

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1 The objective of this investigation was to characterize quantitatively the in¯uence of the rate of increase in blood concentrations on the pharmacodynamics of midazolam in rats. The pharmacodynamics of midazolam were quanti®ed by an integrated pharmacokinetic-pharmacodynamic modelling approach. 2 Using a computer controlled infusion technique, a linear increase in blood concentrations up to 80 ng ml 71 was obtained over di erent time intervals of 1 ± 6 h, resulting in rates of rise of the blood concentrations of respectively, 1.25, 1.00, 0.87, 0.46, 0.34 and 0.20 ng ml 71 min 71 . In one group of rats the midazolam concentration was immediately brought to 80 ng ml 71 and maintained at that level for 4 h. Immediately after the pretreatment an intravenous bolus dose was given to determine the time course of the EEG e ect in conjunction with the decline of midazolam concentrations. 3 The increase in b activity (11.5 ± 30 Hz) of the EEG was used as pharmacodynamic endpoint. For each individual animal the relationship between blood concentration and the EEG e ect could be described by the sigmoidal E max model. After placebo, the values of the pharmacodynamic parameter estimates were E max =82+5 mV, EC 50,u =6.4+0.8 ng ml 71 and Hill factor=1.4+0.1. A bell-shaped relationship between the rate of change of midazolam concentration and the value of EC 50,u was observed with a maximum of 21+5.0 ng ml 71 at a rate of change of 0.46 ng ml 71 min 71 ; lower values of EC 50,u were observed at both higher and lower rates. 4 The ®ndings of this study show that the rate of change in plasma concentrations is an important determinant of the pharmacodynamics of midazolam in rats.

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Agonist‐Dependent Internalization of γ‐Aminobutyric Acid_A/Benzodiazepine Receptors in Chick Cortical Neurons

Cited by 61 publications

References 11 publications

Subunit-Specific Trafficking of GABA_AReceptors during Status Epilepticus

Subunit-Specific Trafficking of GABA_AReceptors during Status Epilepticus

Constitutive GABAA Receptor Endocytosis Is Dynamin-mediated and Dependent on a Dileucine AP2 Adaptin-binding Motif within the β2 Subunit of the Receptor

Rate of change of blood concentrations is a major determinant of the pharmacodynamics of midazolam in rats

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Agonist‐Dependent Internalization of γ‐Aminobutyric AcidA/Benzodiazepine Receptors in Chick Cortical Neurons

Cited by 61 publications

References 11 publications

Subunit-Specific Trafficking of GABAAReceptors during Status Epilepticus

Subunit-Specific Trafficking of GABAAReceptors during Status Epilepticus

Constitutive GABAA Receptor Endocytosis Is Dynamin-mediated and Dependent on a Dileucine AP2 Adaptin-binding Motif within the β2 Subunit of the Receptor

Rate of change of blood concentrations is a major determinant of the pharmacodynamics of midazolam in rats

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Resources

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Agonist‐Dependent Internalization of γ‐Aminobutyric Acid_A/Benzodiazepine Receptors in Chick Cortical Neurons

Subunit-Specific Trafficking of GABA_AReceptors during Status Epilepticus

Subunit-Specific Trafficking of GABA_AReceptors during Status Epilepticus