Inverse but not full benzodiazepine agonists modulate recombinant α6β2γ2 GABAA receptors in transfected human embryonic kidney cells

Kleingoor, Claudia; Ewert, Markus; Blankenfeld, G. von; Seeburg, Peter H.; Kettenmann, Helmut

doi:10.1016/0304-3940(91)90389-b

Cited by 64 publications

(30 citation statements)

References 15 publications

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“…The investigated recombinant receptors containing a, or a6 are not functionally modulated by ethanol [5,8]. Wafford et al have first found an effect of ethanol on recombinant GABA, receptors [9, lo], showing that ethanol sensitivity is associated specifically with a consensus phophorylation site for protein kinase C that occurs in the yZL subunit, and not in the shorter splice variant yZs [11,12], in the mouse recombinant subunit combination ~19, yZ.…”

Section: Methodsmentioning

confidence: 99%

Recombinant GABA_A receptor function and ethanol

1993

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Section: Methodsmentioning

confidence: 99%

Recombinant GABA_A receptor function and ethanol

1993

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“…Based upon a variety of investigations, an argument could be made that the furosemide-sensitive receptor, a BZDinsensitive receptor (Kleingoor et al, 1991), might also be sensitive to ethanol enhancement of GABA function (Harris et al, 1995b, Ticku andBurch, 1980). This view is based upon the inverse agonist, RO15-4513, which binds to the furosemide-sensitive receptor Mhatre et al, 1988), antagonizing the deficit in righting reflex induced by ethanol (Bonetti et al, 1989;Suzdak et al, 1986a; see review by Ticku and Kulkarni, 1988).…”

Section: Argument For An Action Of Ethanol On Bzd-insensitive Gaba a mentioning

confidence: 99%

“…Most important to the concept that zolpidem predicted the action of ethanol on GABA function , ethanol at reasonable concentrations did not alter the effect of GABA responsiveness when the a 1 b 2 g 2L combination was expressed in various cell lines (see Criswell et al, 2003;Kleingoor et al, 1991;Mihic et al, 1994;Mori et al, 2000;Sapp and Yeh, 1998;Sigel et al, 1993) or in oocytes (Harris et al, 1997)Fa contrast to the positive effect found when the a 1 b 1 g 2L subunit combination was expressed in oocytes (Wafford et al, 1991) or L(tk À ) cells (Harris et al, 1995c). Consequently, the view concerning the specificity for ethanol to affect the type-1-BZD receptor directly to enhance GABA function was placed in doubt.…”

Section: In Vitro Examination Of Ethanol Action On Gaba a Receptor Fumentioning

confidence: 99%

A Conceptualization of Integrated Actions of Ethanol Contributing to its GABAmimetic Profile: A Commentary

Criswell

Breese

2005

Neuropsychopharmacol

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Early behavioral investigations supported the contention that systemic ethanol displays a GABAmimetic profile. Microinjection of GABA agonists into brain and in vivo electrophysiological studies implicated a regionally specific action of ethanol on GABA function. While selectivity of ethanol to enhance the effect of GABA was initially attributed an effect on type-1-benzodiazepine (BZD)-GABA A receptors, a lack of ethanol's effect on GABA responsiveness from isolated neurons with this receptor subtype discounted this contention. Nonetheless, subsequent work identified GABA A receptor subtypes, with limited distribution in brain, sensitive to enhancement of GABA at relevant ethanol concentrations. In view of these data, it is hypothesized that the GABAmimetic profile for ethanol is due to activation of mechanisms associated with GABA function, distinct from a direct action on the majority of postsynaptic GABA A receptors. The primary action proposed to account for ethanol's regional specificity on GABA transmission is its ability to release GABA from some, but not all, presynaptic GABAergic terminals. As systemic administration of ethanol increases neuroactive steroids, which can enhance GABA responsiveness, this elevated level of neurosteroids is proposed to magnify the effect of GABA released by ethanol. Additional factors contributing to the degree to which ethanol interacts with GABA function include an involvement of GABA B and other receptors that influence ethanol-induced GABA release, an effect of phosphorylation on GABA responsiveness, and a regional reduction of glutamatergic tone. Thus, an integration of these consequences induced by ethanol is proposed to provide a logical basis for its in vivo GABAmimetic profile.

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“…The benzodiazepine sensitivity of GABA, receptors differs when different a subtypes are combined with p-and y-subunits (Table 2) (12)(13)(14)(15)(16). The alpy-subunits produce diazepam-and zolpidem-sensitive BZ 1 GABA, receptors, a 2 p y -and a3py-subunits produce BZ2a,b GABA, receptors with high diazepam and low zolpidem sensitivity, &Spy-subunits produce BZ2c GABA, receptors with high diazepam sensitivity but zolpidem insensitivity, and 014-or a6py-subunits produce BZ3 GABA, receptors that are benzodiazepine insensitive.…”

Section: Pharmacology Of Recombinant Gabaa Receptorsmentioning

confidence: 99%

“…The distribution of mRNAs in the CNS determined by in situ hybridization is very different for each subunit subtype. For example, the p-subunit is expressed primarily in the retina (17), whereas various a, p, and y subtypes and the single 6 subtype show very different regional as well as developmental distributions (1 [8][9][10][11][12][13][14][15][16][17][18][19][20]. Immunoprecipitation studies have shown that different specific combinations of GABA, receptor-subtypes occur in the different regions of the brain.…”

Section: Pharmacology Of Recombinant Gabaa Receptorsmentioning

confidence: 99%

Acute Cellular Alterations in the Hippocampus After Status Epilepticus

Macdonald

Kapur

1999

Epilepsia

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Summary: The critical, fundamental mechanisms that determine the emergence of status epilepticus from a single seizure and the prolonged duration of status epilepticus are uncertain. However, several general concepts of the pathophysiology of status epilepticus have emerged: (a) the hippocampus is consistently activated during status epilepticus; (b) loss of GABA‐mediated inhibitory synaptic transmission in the hippocampus is critical for emergence of status epilepticus; and, finally (c) glutamatergic excitatory synaptic transmission is important in sustaining status epilepticus. This review focuses on the alteration of GABAergic inhibition in the hippocampus that occurs during the prolonged seizures of status epilepticus. If reduction in GABAergic inhibition leads to development of status epilepticus, enhancement of GABAergic inhibition would be expected to interrupt status epilepticus. Benzodiazepines and barbiturates are both used in the treatment of status epilepticus and both drugs enhance GABAA receptor‐mediated inhibition. However, patients often become refractory to benzodiazepines when seizures are prolonged, and barbiturates are often then used for these refractory cases of status epilepticus. Recent evidence suggests the presence of multiple GABAA receptor isoforms in the hippocampus with different sensitivity to benzodiazepines but similar sensitivity to barbiturates, thus explaining why the two drug classes might have different clinical effects. In addition, rapid functional plasticity of GABAA receptors has been demonstrated to occur during status epilepticus in rats. During status epilepticus, there was a substantial reduction of diazepam potency for termination of the seizures. The loss of sensitivity of the animals to diazepam during status epilepticus was accompanied by an alteration in the functional properties of hippocampal dentate granule cell GABAA receptors. Dentate granule cell GABAA receptor currents from rats undergoing status epilepticus had reduced sensitivity to diazepam and zinc but normal sensitivity to GABA and pentobarbital. Therefore, the prolonged seizures of status epilepticus rapidly altered the functional properties of hippocampal dentate granule cell GABAA receptors, possibly explaining why benzodiazepines and barbiturates may not be equally effective during treatment of the prolonged seizures of status epilepticus. A comprehensive understanding of the cellular and molecular events leading to the development, maintenance, and cytotoxicity of status epilepticus should permit development of more effective treatment strategies and reduction in the mortality and morbidity of status epilepticus.

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Inverse but not full benzodiazepine agonists modulate recombinant α6β2γ2 GABAA receptors in transfected human embryonic kidney cells

Cited by 64 publications

References 15 publications

Recombinant GABA_A receptor function and ethanol

Recombinant GABA_A receptor function and ethanol

A Conceptualization of Integrated Actions of Ethanol Contributing to its GABAmimetic Profile: A Commentary

Acute Cellular Alterations in the Hippocampus After Status Epilepticus

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Inverse but not full benzodiazepine agonists modulate recombinant α6β2γ2 GABAA receptors in transfected human embryonic kidney cells

Cited by 64 publications

References 15 publications

Recombinant GABAA receptor function and ethanol

Recombinant GABAA receptor function and ethanol

A Conceptualization of Integrated Actions of Ethanol Contributing to its GABAmimetic Profile: A Commentary

Acute Cellular Alterations in the Hippocampus After Status Epilepticus

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Recombinant GABA_A receptor function and ethanol

Recombinant GABA_A receptor function and ethanol