GABA‐site antagonism and pentobarbital actions do not depend on the <i>α</i>‐subunit type in the recombinant rat GABA<sub>A</sub> receptor

Rahman, Mozibur; Zhu, Di; Lindblad, Charlotte; Johansson, Ingvar; Holmberg, Ellinor; Isaksson, Monica; Taube, Magdalena; Bäckström, Torbjörn; Wang, M.‐D.

doi:10.1111/j.1748-1716.2006.01593.x

Cited by 10 publications

(11 citation statements)

References 39 publications

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“…We have reported earlier that the GABA site antagonism and pentobarbital action on the recombinant rat GABA A receptor do not depend on the α‐ and β‐subunits 31 . In the present study, we found that the Hα 4 β 3 γ 2S receptor conferred lower agonist efficacies on GABA sites compared with the Hα 4 β 2 γ 2S receptor in terms of significantly reduced I max (Fig.…”

Section: Resultssupporting

confidence: 60%

“…Drugs were bath applied from a common tip via a gravity‐driven multibarrel drug‐delivery system (ValveLink 16 pinch valve perfusion system controlled by a Valvelink 16 controller; AutoMate Scientific, San Francisco, CA, USA). Cells were clamped at −70 mV for all experiments and currents at the end of the 20 s drug application were measured for quantification of current amplitudes 30,31 …”

Section: Methodsmentioning

confidence: 99%

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Agonist function of the recombinant α₄β₃δ GABA_A receptor is dependent on the human and rat variants of the α₄‐subunit

Wang

Rahman

Johansson

et al. 2010

Clin Exp Pharma Physio

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1. It is known that the alpha(4)-subunit is likely to occur in the brain predominantly in alpha(4)beta(3)delta receptors at extrasynaptic sites. Recent studies have revealed that the alpha(1)-, alpha(4)-, gamma(2)- and delta-subunits may colocalize extrasynaptically in dentate granule cells of the hippocampus. In the present study, we characterized a series of recombinant GABA(A) receptors containing human (H) and rat (R) alpha(1)/alpha(4)-, beta(2)/beta(3)- and gamma(2S)/delta-subunits in Xenopus oocytes using the two-electrode voltage-clamp technique. 2. Both H alpha(1)beta(3)delta and H alpha(4)beta(3)gamma(2S) receptors were sensitive to activation by GABA and pentobarbital. Contrary to earlier findings that the alpha(4)beta(3)delta combination was more sensitive to agonist action than the alpha(4)beta(3)gamma(2S) receptor, we observed extremely small GABA- and pentobarbital-activated currents at the wild-type H alpha(4)beta(3)delta receptor. However, GABA and pentobarbital activated the wild-type R alpha(4)beta(3)delta receptor with high potency (EC(50) = 0.5 +/- 0.7 and 294 +/- 5 micromol/L, respectively). 3. Substituting the H alpha(4) subunit with R alpha(4) conferred a significant increase in activation on the GABA and pentobarbital site in terms of reduced EC(50) and increased I(max). When the H alpha(4) subunit was combined with the R beta(3) and R delta subunit in a heteropentameric form, the amplitude of GABA- and pentobarbital-activated currents increased significantly compared with the wild-type H alpha(4)beta(3)delta receptor. 4. Thus, the results indicate that the R alpha(4)beta(3)delta, H alpha(1)beta(3)delta and H alpha(4)beta(3)gamma(2S) combinations may contribute to functions of extrasynaptic GABA(A) receptors. The presence of the R alpha(4) subunit at recombinant GABA(A) receptors containing the delta-subunit is a strong determinant of agonist action. The recombinant H alpha(4)beta(3)delta receptor is a less sensitive subunit composition in terms of agonist activation.

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Section: Resultssupporting

confidence: 60%

Section: Methodsmentioning

confidence: 99%

Agonist function of the recombinant α₄β₃δ GABA_A receptor is dependent on the human and rat variants of the α₄‐subunit

Wang

Rahman

Johansson

et al. 2010

Clin Exp Pharma Physio

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“…The predominant synaptic GABA A receptor isoform is composed of two ␣ 1 , two ␤ 2 , and a ␥ 2 subunits. Upon deletion of the ␥ 2 subunit and the inclusion of ␣ 4 , ␣ 5 , ␦, or ε subunits, GABA A receptors have an altered affinity for GABA and allosteric modulators, such as pentobarbital (7,10,23,53). We speculate that altered subunit stoichiometry provides a plausible mechanism for the pentobarbital insensitivity described here.…”

Section: Discussionmentioning

confidence: 76%

Hibernation induces pentobarbital insensitivity in medulla but not cortex

Hengen¹,

Behan²,

Carey³

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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Hengen KB, Behan M, Carey HV, Jones MV, Johnson SM. Hibernation induces pentobarbital insensitivity in medulla but not cortex. Am J Physiol Regul Integr Comp Physiol 297: R1028-R1036, 2009. First published August 12, 2009 doi:10.1152/ajpregu.00239.2009.-The 13-lined ground squirrel (Ictidomys tridecemlineatus), a hibernating species, is a natural model of physiological adaption to an extreme environment. During torpor, body temperature drops to 0 -4°C, and the cortex is electrically silent, yet the brain stem continues to regulate cardiorespiratory function. The mechanisms underlying selective inhibition in the brain during torpor are not known. To test whether altered GABAergic function is involved in regional and seasonal differences in neuronal activity, cortical and medullary slices from summer-active (SA) and interbout aroused (IBA) squirrels were placed in a standard in vitro recording chamber. Silicon multichannel electrodes were placed in cortex, ventral respiratory column (VRC), and nucleus tractus solitarius (NTS) to record spontaneous neuronal activity. In slices from IBA squirrels, bath-applied pentobarbital sodium (300 M) nearly abolished cortical neuronal activity, but VRC and NTS neuronal activity was unaltered. In contrast, pentobarbital sodium (300 M) nearly abolished all spontaneous cortical, VRC, and NTS neuronal activity in slices from SA squirrels. Muscimol (20 M; GABAA receptor agonist) abolished all neuronal activity in cortical and medullary slices from both IBA and SA squirrels, thereby demonstrating the presence of functional GABAA receptors. Pretreatment of cortical slices from IBA squirrels with bicuculline (100 M; GABAA receptor antagonist) blocked pentobarbital-dependent inhibition of spontaneous neuronal activity. We hypothesize that GABAA receptors undergo a seasonal modification in subunit composition, such that cardiorespiratory neurons are uniquely unaffected by surges of an endogenous positive allosteric modulator.␥-aminobutyric acid receptors; ventral respiratory groups; nucleus tractus solitarius; respiratory control DURING WINTER HIBERNATING, mammals enter a state of torpor, defined by dramatically reduced metabolic and physical activity and low body temperature (T b ). The torpid state is interrupted periodically by interbout arousals to euthermia (T b ϭ 37°C) that generally last less than 24 h (3, 8). During torpor bouts, T b drops to just above ambient temperature and can approach 0°C, and respiration and heart rate drop as low as 1% of euthermic values (39,71). Neurons in the cortex, hippocampus, and thalamus are electrically silent in torpid hibernators (14, 67). Despite evidence for global forebrain depression, torpid hibernators maintain a robust, neuronally regulated cardiorespiratory output (37,25,41), suggesting that respiratoryand cardiovascular-related neurons in the brain stem remain active. The mechanisms that selectively depress the forebrain during hibernation are not well understood and may contribute to hibernators' unique ability to survive ischemia, hyp...

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“…Classical benzodiazepines such as midazolam and diazepam are fairly nonselective, showing equally high efficacy at GABA A receptors containing alpha 1,2,3 and 5 subunits but no appreciable affinity at physiologically relevant concentrations for alpha 4 and 6 containing receptors (Harris et al, 1997). Likewise, barbiturates are fairly nonselective positive allosteric modulation of GABA A receptors (Harris et al, 1997; Pistis et al, 1997; Rahman et al, 2006). These results indicate that GABA A positive modulation is important for the discriminative stimulus effects of TCE, but do not suggest which subunits are involved.…”

Section: Discussionmentioning

confidence: 99%

GABAA-positive modulator selective discriminative stimulus effects of 1,1,1-trichloroethane vapor

Shelton

Nicholson

2012

Drug and Alcohol Dependence

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Background The abuse-related behavioral effects of inhalant vapors are poorly understood but probably involve multiple neurotransmitter receptor mechanisms. The present study examined the receptor systems responsible for transducing the discriminative stimulus of the abused chlorinated hydrocarbon 1,1,1-trichloroethane (TCE) in mice. Methods Thirty mice were trained to discriminate 10 min of 12000 ppm TCE vapor exposure from air using an operant procedure. Substitution tests were then conduced with positive GABAA receptor modulators and/or NMDA receptor antagonists. Results The nonselective benzodiazepines midazolam and diazepam produced 62% and 61% and the barbiturate pentobarbital produced 68% TCE-lever selection. Zaleplon, an alpha1 subunit-preferring positive GABAA receptor benzodiazepine-site positive modulator resulted in 29% TCE-lever selection. The direct extrasynaptic GABAA agonist gaboxodol (THIP) and the GABA reuptake inhibitor tiagabine failed to substitute for TCE. No substitution was elicited by a competitive (CGS-19755), noncompetitive (dizocilpine) or glycine-site (L701,324) NMDA antagonist. The mixed benzodiazepine/noncompetitive NMDA antagonist anesthetic Telazol and the anticonvulsant valproic acid exhibited low levels of partial substitution for TCE (38% and 39% respectively). Ethanol and nitrous oxide failed to substitute for TCE. Conclusions The results suggest that the discriminative stimulus effects of TCE are fairly selectively mediated by positive modulation of GABAA receptors. The failure of gaboxadol to substitute and the poor substitution by zaleplon suggests that extrasynaptic GABAA receptors as well as GABAA receptors containing alpha 1 subunits and are not involved in transducing the discriminative stimulus of TCE. Studies with additional GABAA benzodiazepine-site positive modulators will be necessary to confirm and extend these findings.

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GABA‐site antagonism and pentobarbital actions do not depend on the α‐subunit type in the recombinant rat GABA_A receptor

Cited by 10 publications

References 39 publications

Agonist function of the recombinant α₄β₃δ GABA_A receptor is dependent on the human and rat variants of the α₄‐subunit

Agonist function of the recombinant α₄β₃δ GABA_A receptor is dependent on the human and rat variants of the α₄‐subunit

Hibernation induces pentobarbital insensitivity in medulla but not cortex

GABAA-positive modulator selective discriminative stimulus effects of 1,1,1-trichloroethane vapor

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GABA‐site antagonism and pentobarbital actions do not depend on the α‐subunit type in the recombinant rat GABAA receptor

Cited by 10 publications

References 39 publications

Agonist function of the recombinant α4β3δ GABAA receptor is dependent on the human and rat variants of the α4‐subunit

Agonist function of the recombinant α4β3δ GABAA receptor is dependent on the human and rat variants of the α4‐subunit

Hibernation induces pentobarbital insensitivity in medulla but not cortex

GABAA-positive modulator selective discriminative stimulus effects of 1,1,1-trichloroethane vapor

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GABA‐site antagonism and pentobarbital actions do not depend on the α‐subunit type in the recombinant rat GABA_A receptor

Agonist function of the recombinant α₄β₃δ GABA_A receptor is dependent on the human and rat variants of the α₄‐subunit

Agonist function of the recombinant α₄β₃δ GABA_A receptor is dependent on the human and rat variants of the α₄‐subunit