Modulation of the GABA
            <sub>A</sub>
            receptor by progesterone metabolites

Callachan, Helen; Cottrell, G. A.; Hather, N. Y.; Lambert, Jeremy J.; Nooney, Janet M.; Peters, John A.

doi:10.1098/rspb.1987.0049

Cited by 206 publications

(48 citation statements)

References 25 publications

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“…Collectively, these results are consistent with propofol in some way activating the GABAA receptor-chloride channel complex. Similar observations have been made for anaesthetic steroids Callachan et al, 1987;Lambert et al, 1987), the hypnotic and anticonvulsant chlor-methiazole (Hales & Lambert, 1988a) the intravenous general anaesthetic propanidid (Peters & Lambert, unpublished observations), and pentobarbitone (e.g. Owen et al, 1986;Peters et al, 1988;Robertson, 1989).…”

Section: Discussionmentioning

confidence: 51%

“…Visual inspection of the figure suggests that propofol (1.7,UM) has little effect on the GABA single channel amplitudes (see Table 1 The mean chord conductances (pS) of GABA channels calculated assuming a reversal potential of 0 mV (Bormann et al, 1987 Figure 4c). Electrophysiological (Callachan et al, 1987;Cottrell et al, 1987;Lambert et al, 1987) and radioligand binding experiments (Gee et al, 1988;Peters et al, 1988;Kirkness, 1989;Turner et al, 1989) suggest that anaesthetic steroids and barbiturates bind to different sites on the GABAA receptors to potentiate the action of GABA. In confirmation of previous results (Peters et al, 1988) the anaesthetic steroid 5fi-pregnan3a-ol-20-one (0.5 pM) produced a marked potentiation of both GABA currents (856 + 194% of control, n = 10) and pentobarbitone currents (906 + 121% of control, n = 16).…”

Section: Resultsmentioning

confidence: 99%

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The actions of propofol on inhibitory amino acid receptors of bovine adrenomedullary chromaffin cells and rodent central neurones

Hales

Lambert

1991

British J Pharmacology

329

226

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University of Dundee, Dundee DD1 9SY1 The interaction of the intravenous general anaesthetic propofol (2,6-diisopropylphenol) with the GABAA receptor has been investigated in voltage-clamped bovine chromaffin cells and rat cortical neurones in cell culture. Additionally, the effects of propofol on the glycine and GABAA receptors of murine spinal neurones were determined. 2 Propofol (1.7-16.8 uM) reversibly and dose-dependently potentiated the amplitude of membrane currents elicited by GABA (100puM) applied locally to bovine chromaffin cells. Intracellular application of propofol (16.8 pM) was ineffective. In rat cortical neurones and murine spinal neurones, extracellular application of 8.4pM and 1.7-16.8/pM propofol respectively produced a potentiation of GABA-evoked currents qualitatively similar to that seen in the bovine chromaffin cell. 3 The potentiation by propofol (1.7,UM) was not associated with a change in the reversal potential of the GABA-evoked whole cell current. On outside-out membrane patches isolated from bovine chromaffin cells, propofol (1.7,UM) had little or no effect on the GABA single channel conductances, but greatly increased the probability of the GABA-gated channel being in the conducting state. 4 The potentiation of GABA-evoked whole cell currents by propofol (1.7 pM) was not influenced by the benzodiazepine antagonist flumazenil (0.3 pM). A concentration of propofol (1.7/pM) that substantially potentiated GABA currents had little effect on currents induced by the activation of the GABAA receptor by pentobarbitone (1 mM). 5 Bath application of propofol (8.4-252 pM), to bovine chromaffin cells voltage clamped at -60 mV, induced an inward current associated with an increase in membrane current noise on all cells sensitive to GABA. Intracellular application of propofol (16.8,UM) was ineffective in this respect. Local application of propofol (600pM) induced whole cell currents with a reversal potential dependent upon the CF-gradient across the cell membrane.6 On outside-out membrane patches formed from bovine chromaffin cells, propofol (30M) induced single channels with mean chord conductances of 29 and 12 pS. The frequency of propofol channels was greatly reduced by coapplication of 1 CM bicuculline. Under identical ionic conditions, GABA (1 pM) activated single channels with mean chord conductances of 33, 16 and 10pS.7 Bath applied propofol (0.84-16.8 juM) dose-dependently potentiated strychnine-sensitive currents evoked by glycine (100,Mm) in murine spinal neurones.8 The relevance of the present results to the general anaesthetic action of propofol is discussed.

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Section: Discussionmentioning

confidence: 51%

Section: Resultsmentioning

confidence: 99%

The actions of propofol on inhibitory amino acid receptors of bovine adrenomedullary chromaffin cells and rodent central neurones

Hales

Lambert

1991

British J Pharmacology

329

226

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“…While reports suggested a direct interaction between ethanol and neurosteroids on GABA A receptor function (Akk and Steinbach, 2003;Criswell et al, 1999), recent data from our laboratory questions this observation (Criswell et al, 2003). Further, it should be recognized that the concentration of neurosteroid following ethanol (o100 nM) is likely insufficient to have a direct effect on GABA A receptors to gate current in the absence of GABA (Callachan et al, 1987;Cottrell et al, 1987;Puia et al, 1990). This circumstance minimizes the possibility that a direct activation of GABA A receptor function by neurosteroids is responsible for the neurosteroid contribution to the GABAmimetic profile of ethanol.…”

Section: Neurosteroid Involvement In the Gabamimetic Profile Of Ethanmentioning

confidence: 53%

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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“…A hydrogen bond donor at C3 in the alpha configuration (3α-OH) is critical for GABA A receptor activity and anesthesia, as is a hydrogen-bond acceptor attached to C17 on the β face of the steroid (Callachan et al, 1987;Covey et al, 2001;Majewska et al, 1986;Phillipps, 1975). Activity at GABA A receptors is not markedly altered by the stereochemistry at C5; either 5α-or 5β reduction at this position (combined with the other requirements above) results in active steroids.…”

Section: Overview Of Neurosteroid Interactions With Gaba a Receptorsmentioning

confidence: 99%

“…Like many GABA-receptor potentiators, including barbiturates, etomidate, and propofol, neuroactive steroids augment the whole-cell response to low concentrations of GABA (Callachan et al, 1987;Cottrell et al, 1987;Majewska et al, 1986;Shu et al, 2004). Depending on subunit composition of the receptor and agonist, another important effect of steroids is to increase the efficacy of agonist actions (Bianchi & Macdonald, 2003;Maksay et al, 2000;Wohlfarth et al, 2002).…”

Section: Overview Of Neurosteroid Interactions With Gaba a Receptorsmentioning

confidence: 99%

Mechanisms of neurosteroid interactions with GABAA receptors

Akk¹,

Covey²,

Evers³

et al. 2007

Pharmacology & Therapeutics

147

166

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Neuroactive steroids have some of their most potent actions by augmenting the function of GABA A receptors. Endogenous steroid actions on GABA A receptors may underlie important effects on mood and behavior. Exogenous neuroactive steroids have potential as anesthetics, anticonvulsants, and neuroprotectants. We have taken multiple approaches to understand more completely the interaction of neuroactive steroids with GABA A receptors. We have developed many novel steroid analogues in this effort. Recent work has resulted in synthesis of new enantiomer analogue pairs, novel ligands that probe various properties of the steroid pharmacophore, fluorescent neuroactive steroid analogues, and photoaffinity labels. Using these tools, combined with receptor binding and electrophysiological assays, we have begun to untangle the complexity of steroid actions at this important class of ligand-gated ion channel.

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Modulation of the GABA _A receptor by progesterone metabolites

Cited by 206 publications

References 25 publications

The actions of propofol on inhibitory amino acid receptors of bovine adrenomedullary chromaffin cells and rodent central neurones

The actions of propofol on inhibitory amino acid receptors of bovine adrenomedullary chromaffin cells and rodent central neurones

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

Mechanisms of neurosteroid interactions with GABAA receptors

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Modulation of the GABA A receptor by progesterone metabolites

Cited by 206 publications

References 25 publications

The actions of propofol on inhibitory amino acid receptors of bovine adrenomedullary chromaffin cells and rodent central neurones

The actions of propofol on inhibitory amino acid receptors of bovine adrenomedullary chromaffin cells and rodent central neurones

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

Mechanisms of neurosteroid interactions with GABAA receptors

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Product

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Modulation of the GABA _A receptor by progesterone metabolites