Kinetic properties of the pentobarbitone‐gated chloride current in frog sensory neurones.

Akaike, Norio; Maruyama, Tadashi; Tokutomi, Naofumi

doi:10.1113/jphysiol.1987.sp016861

Cited by 83 publications

(57 citation statements)

References 42 publications

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“…At higher concentrations, pentobarbital directly activates GABA A receptors (Nicoll and Wojtowicz, 1980;Schulz and Macdonald, 1981;Krampfl et al, 2002). At millimolar concentrations, pentobarbital inhibits GABA A receptor function, probably through a low-affinity open channel block mechanism (Akaike et al, 1987;Rho et al, 1996;Akk and Steinbach, 2000). These properties of pentobarbital (positive allosteric modulation, direct agonism, and open channel block) are similar to those reported for certain neurosteroids (Lambert et al, 1995;Rupprecht and Holsboer, 1999).…”

supporting

confidence: 58%

Pentobarbital Differentially Modulates α1β3δ and α1β3γ2L GABA_AReceptor Currents

Feng¹,

Bianchi²,

Macdonald³

2004

Mol Pharmacol

112

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GABA A receptors are modulated by a variety of compounds, including the neurosteroids and barbiturates. Although the effects of barbiturates on ␣␤␥ isoforms, thought to dominate phasic (synaptic) GABAergic inhibition, have been extensively studied, the effects of pentobarbital on kinetic properties of ␣␤␦ GABA A receptors, thought to mediate tonic (extra-or perisynaptic) inhibition, are unknown. Using ultrafast drug delivery and single channel recording techniques, we demonstrate isoform-specific pentobarbital modulation of low-efficacy, minimally desensitizing ␣1␤3␦ currents and high-efficacy, rapidly desensitizing ␣1␤3␥2L currents. Specifically, with saturating concentrations of GABA, pentobarbital substantially potentiated peak ␣1␤3␦ receptor currents but failed to potentiate peak ␣1␤3␥2L receptor currents. Also, pentobarbital had opposite effects on the desensitization of ␣1␤3␦ (increased) and ␣1␤3␥2L (decreased) receptor currents evoked by saturating GABA. Pentobarbital increased steady-state ␣1␤3␦ receptor single channel open duration primarily by introducing a longer duration open state, whereas for ␣1␤3␥2L receptor channels, pentobarbital increased mean open duration by increasing the proportion and duration of the longest open state. The data support previous suggestions that GABA may be a partial agonist at ␣␤␦ isoforms, which may render them particularly sensitive to allosteric modulation. The remarkable increase in gating efficacy of ␣1␤3␦ receptors suggests that ␣␤␦ isoforms, and by inference tonic forms of inhibition, may be important targets for barbiturates.

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supporting

confidence: 58%

Pentobarbital Differentially Modulates α1β3δ and α1β3γ2L GABA_AReceptor Currents

Feng¹,

Bianchi²,

Macdonald³

2004

Mol Pharmacol

112

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“…This is comparable to another ligand gated ion channel, the nicotinic acetylcholine receptor, which is activated by physostigmine via a site separate from the acetylcholine binding site (Okonjo et al, 1991;Lena & Changeux, 1993). Krishek & Smart (1995) (Akaike et al, 1987;Peters, 1988;Robertson, 1989) have reported on the washout phenomenon observed with high concentrations of pentobarbitone. This effect, which has been termed 'bounce' or 'hump', involves a marked transient increase in current during the washout period of high concentrations of pentobarbitone.…”

Section: Discussionmentioning

confidence: 98%

Barbiturate interactions at the human GABA_A receptor: dependence on receptor subunit combination

Thompson

Whiting

Wafford

1996

British J Pharmacology

169

114

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1 Human GABAA receptors containing different and subunits with a y2s subunit were expressed in Xenopus oocytes and the effects of pentobarbitone on these subunit combinations were examined by electrophysiological recording of GABA currents with the two-electrode voltage-clamp method. 2 Pentobarbitone has previously been shown to have three actions on GABAA receptors: a potentiation of GABA responses, a direct activation of GABAA receptors and, at high concentrations, a block of the GABA chloride channel. In this study pentobarbitone activity consisted of the above mentioned three components on all the subunit combinations tested. However, the affinities and efficacies varied with receptor subtype. 3 Potentiation of GABA by pentobarbitone occurred over the same concentration-range for all the subunits with affinities in the range of 20-35 tiM. The degree of potentiation obtained, however, varied from 236% of GABA EC20 on al/#2y2s to 536% on a6fl2y2s.4 Examination of the direct effect of pentobarbitone revealed that the type of a subunit present determines both the degree of affinity and efficacy obtained. Receptors containing an cc6 subunit produced maximum direct responses to pentobarbitone larger than that obtainable with maximum GABA (150% to 170% of maximum GABA). The maximum direct pentobarbitone response obtainable with other a subunits ranged between 45% of maximum GABA for ac5f2y2s to 82% for a2/32y2s. The affinity of the direct action of pentobarbitone on a6/32y2s was 58 tiM compared to affinities for the other subunits ranging from 139 pM on a2fl2y2s to 528 gM on ac5f2y2s.5 The type of subunit present did not influence the direct action of pentobarbitone to the same extent as the a subunit. There were no significant differences between affinity or efficacy on oocytes expressing a6 and y2s with /31, /32 or P3. Affinities and efficacies on oocytes expressing al and y2s with PI, /2 or /3 were significantly different with pentobarbitone having a higher affinity and efficacy on al/33y2s followed by al/32y2s and then al/3ly2s. 6 The direct effect of pentobarbitone was blocked by picrotoxin but not by competitive antagonists, such as bicuculline or SR95531, indicating that the direct agonist activity of pentobarbitone was not mediated via the GABA binding site. 7 For the first time the influence of the various a and subunits on the effects of pentobarbitone were demonstrated. The results indicate that GABAA receptors containing a6 subunits have both a higher affinity and efficacy for direct activation by pentobarbitone, and reveal that pentobarbitone binds to more than one site on the GABAA receptor, and these are dependent on receptor subunit composition.

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“…As well as exerting agonist actions, the presence of Fthe AVM-'bounce' on washout of pentobarbitone suggested y and comthat this compound may also be blocking GABA antagonist receptor/channels. Bounce has also been observed the antagowith pentobarbitone by Akaike et al (1985Akaike et al ( , 1987, and these authors have proposed a channel blocking mechanism to account for this phenomenon. Adams (1975) observed a bounce on washout of high concentrations of certain nicotinic agonists from frog muscle and suggested that these current surges were due to the agonist binding to 'hypothetical nonreceptor sites' and that the agonists were released from these reservoirs during washout.…”

Section: Halothane Ketamine and Diazepammentioning

confidence: 92%

Actions of anaesthetics and avermectin on GABA_A chloride channels in mammalian dorsal root ganglion neurones

Robertson

1989

British J Pharmacology

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1 The y-aminobutyric acid (GABA)-mimetic actions of some anaesthetics and the antehelminthic avermectin B1a were examined on freshly isolated mammalian dorsal root ganglion (DRG) neurones by use of suction electrodes and a single electrode voltage clamp.2 Pentobarbitone (60yM-3mM), chloralose (600yM-1mM), etomidate (10-100 pM), alphaxalone (10-60pM) and avermectin (10-60pM) directly activated chloride channels in GABA-sensitive DRG neurones. The agonist action was sensitive to block by bicuculline and picrotoxinin. 3 Steady-state current-voltage (I-V) curves for the anaesthetics were either linear, or rectified in the opposite direction to steady-state I-V curves obtained with GABA. Current relaxations in response to voltage jumps were also of the opposite direction. An extra surge of current ('bounce') was commonly observed on washout of some of these agonists. 4 Pentobarbitone was ineffective as an agonist at alkali pH (10.4 and 9.4), but was approximately twice as effective at acid (5.4) than at normal (7.4) pH values. 5 These results suggest that some anaesthetics and avermectin are capable of 'blocking' GABA channels in addition to activating them.

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Kinetic properties of the pentobarbitone‐gated chloride current in frog sensory neurones.

Cited by 83 publications

References 42 publications

Pentobarbital Differentially Modulates α1β3δ and α1β3γ2L GABA_AReceptor Currents

Pentobarbital Differentially Modulates α1β3δ and α1β3γ2L GABA_AReceptor Currents

Barbiturate interactions at the human GABA_A receptor: dependence on receptor subunit combination

Actions of anaesthetics and avermectin on GABA_A chloride channels in mammalian dorsal root ganglion neurones

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Kinetic properties of the pentobarbitone‐gated chloride current in frog sensory neurones.

Cited by 83 publications

References 42 publications

Pentobarbital Differentially Modulates α1β3δ and α1β3γ2L GABAAReceptor Currents

Pentobarbital Differentially Modulates α1β3δ and α1β3γ2L GABAAReceptor Currents

Barbiturate interactions at the human GABAA receptor: dependence on receptor subunit combination

Actions of anaesthetics and avermectin on GABAA chloride channels in mammalian dorsal root ganglion neurones

Contact Info

Product

Resources

About

Pentobarbital Differentially Modulates α1β3δ and α1β3γ2L GABA_AReceptor Currents

Pentobarbital Differentially Modulates α1β3δ and α1β3γ2L GABA_AReceptor Currents

Barbiturate interactions at the human GABA_A receptor: dependence on receptor subunit combination

Actions of anaesthetics and avermectin on GABA_A chloride channels in mammalian dorsal root ganglion neurones