The Effects of Isoflurane on Desensitized Wild-Type and ??1(S270H) ??-Aminobutyric Acid Type A Receptors

Hall, Alex R.; Rowan, Kathleen C.; Stevens, Renna J.; Kelley, Jill C.; Harrison, Neil L.

doi:10.1213/01.ane.0000111108.78745.ad

Cited by 21 publications

(14 citation statements)

References 24 publications

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“…One possibility is that desensitization is reduced. This notion is supported by prior work that showed slower desensitization or potentiation of steady-state currents elicited by saturating GABA in the presence of some anesthetic drugs Hall et al, 2004). Potentiation of steady-state currents from receptors activated by low concentrations of GABA additionally includes an effect on channel gating.…”

Section: Discussionsupporting

confidence: 60%

Synaptic-Type α1β2γ2L GABA_A Receptors Produce Large Persistent Currents in the Presence of Ambient GABA and Anesthetic Drugs

Li¹

2015

Mol Pharmacol

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Synaptic GABA A receptors respond to synaptically released GABA and are considered to be unaffected by the low levels of ambient transmitter in the brain. We show that synaptic-type a1b2g2L GABA A receptors expressed in HEK293 cells respond with large steady-state currents to combinations of a low concentration (0.5 mM) of GABA and clinically used GABAergic modulators propofol, etomidate, or pentobarbital or the steroid alphaxalone. At a maximally effective concentration of modulator, the current levels at the end of 2-minute applications of drug combinations were .10% of the peak response to saturating GABA. In the absence of modulators, 0.5 mM GABA generated a steady-state response of 1% of the peak response to saturating GABA. The concentrationresponse curves for enhancement of steady-state currents by propofol, etomidate, pentobarbital, or alphaxalone were at similar or lower drug concentrations compared with concentration-response relationships for enhancement of peak responses. We propose that modulation of tonically activated synaptic-type GABA A receptors contributes to the clinical actions of sedative drugs.

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Section: Discussionsupporting

confidence: 60%

Synaptic-Type α1β2γ2L GABA_A Receptors Produce Large Persistent Currents in the Presence of Ambient GABA and Anesthetic Drugs

Li¹

2015

Mol Pharmacol

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“…We hypothesize that the negative effects of these anesthetic agents results in part from their ability to activate GABA A receptor (Hall et al, 2004;Haseneder et al, 2002). In the neonatal mammalian hippocampus, activation of the GABA A receptor leads to chloride efflux and membrane depolarization sufficient to open voltage sensitive calcium channels (Leinekugel et al, 1995;LoTurco et al, 1995;Obrietan and van den Pol, 1995).…”

Section: Neonatal Anesthetic Action Results In Gaba-mediated Excitationmentioning

confidence: 99%

“…Phenobarbital, a potent anticonvulsant/barbiturate, binds directly to the GABA A receptor, resulting in enhanced receptor activation (Czapinski et al, 2005). The inhalant isoflurane has been documented to enhance GABA A receptor activity and increase the number of GABA A -mediated postsynaptic potentials (Hall et al, 2004;Haseneder et al, 2002). Findings from the present study are consistent with work documenting the ability of excessive activation of the GABA A receptor in the developing brain to induce hippocampal cell death, decrements in hippocampal-dependent behavioral performance, and enhanced calcium influx in primary cultures of hippocampal neurons (Nuñez et al, 2003a;Nuñez et al, 2003b;Nuñez and McCarthy, 2003;Nuñez et al, 2005).…”

Section: Neonatal Anesthetic Action Results In Gaba-mediated Excitationmentioning

confidence: 99%

Response to neonatal anesthesia: Effect of sex on anatomical and behavioral outcome

2008

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Numerous studies have documented the consequences of exposure to anesthesia in models of term and post-term infants, evaluating the incidence of cell loss, physiological alterations and cognitive dysfunction. However, surprisingly few studies have investigated the effect of anesthetic exposure on outcomes in newborn rodents, the developmental equivalent of premature human infants. This is critical given that one out of every eight babies born in the United States is premature, with an increased prevalence of surgical procedures required in these individuals. Also, no studies have investigated if the genetic sex of the individual influences the response to neonatal anesthesia. Using the newborn rat as the developmental equivalent of the premature human, we documented the effect of a single bout of exposure to either the inhalant isoflurane or the injectable barbiturate phenobarbital on hippocampal anatomy, hippocampal dependent behavioral performance and normal developmental endpoints in male and female rats. While both forms of anesthesia led to significant decrements in cognitive abilities, along with a significant reduction in volume and neuron number in the hippocampus in adulthood, the decrements were significantly greater in males than in females. Interestingly, the deleterious effects of anesthesia were manifest on developmental measures including surface righting and forelimb grasp, but were not evident on basic physiological parameters including body weight or suckling. These findings point to the hazardous effects of exposure to anesthesia on the developing central nervous system and the particular sensitivity of males to deficits.

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“…5B), a concentration within a factor of 2 of that enhancing [ 3 H]muscimol binding (Fig. 2C) but ϳ5-fold higher than the electrophysiological EC 50 for GABA A R potentiation (27,28). In contrast, neither ethanol at a concentration as high as 170 mM (Fig.…”

Section: Numerous Chemical Classes Of General Anesthetics Modulate [ mentioning

confidence: 86%

Numerous Classes of General Anesthetics Inhibit Etomidate Binding to γ-Aminobutyric Acid Type A (GABAA) Receptors

Chiara

Cohen

et al. 2010

Journal of Biological Chemistry

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Enhancement of ␥-aminobutyric acid type A receptor (GABA A R)-mediated inhibition is a property of most general anesthetics and a candidate for a molecular mechanism of anesthesia. Intravenous anesthetics, including etomidate, propofol, barbiturates, and neuroactive steroids, as well as volatile anesthetics and long-chain alcohols, all enhance GABA A R function at anesthetic concentrations. The implied existence of a receptor site for anesthetics on the GABA A R protein was supported by identification, using photoaffinity labeling, of a binding site for etomidate within the GABA A R transmembrane domain at the ␤-␣ subunit interface; the etomidate analog Inhibition by barbiturates, which was pharmacologically specific and stereospecific, and by propofol was only partial, consistent with allosteric interactions, whereas isoflurane inhibition was nearly complete, apparently competitive. Protein sequencing showed that propofol inhibited to the same extent the photolabeling of ␣1Met-236 and ␤Met-286. These results indicate that several classes of general anesthetics modulate etomidate binding to the GABA A R: isoflurane binds directly to the site with millimolar affinity, whereas propofol and barbiturates inhibit binding but do not bind in a mutually exclusive manner with etomidate. ␥-Aminobutyric acid type A receptors (GABA A Rs) 3 are major mediators of brain inhibitory neurotransmission and participate in most circuits and behavioral pathways relevant to normal and pathological function. Their regulation may underlie many psychiatric/neurological disorders. GABA A Rs are subject to modulation by endogenous neurosteroids, as well as myriad clinically important central nervous system drugs, including general anesthetics, benzodiazepines, and ethanol (1-3). The mechanism of GABA A R modulation by these different classes of drugs is of major interest, including the localization of their binding sites in the receptor.Each GABA A R is made up of five homologous subunits that associate around a central axis that forms the ion channel. Each subunit consists of a large extracellular N-terminal domain, a transmembrane domain made up of a loose bundle of four transmembrane ␣-helices, and a cytoplasmic domain made up of the amino acids located in the primary structure between the M3 and M4 helices. In an ␣ 2 ␤ 2 ␥ GABA A R, the neurotransmitter-binding sites are located in the extracellular domain at the interfaces between the ␤ and ␣ subunits, two sites per receptor, whereas the benzodiazepine sites are at an equivalent position at the ␣-␥ subunit interface, one per receptor (4).Most general anesthetics enhance GABA A R responses in vitro at concentrations that produce immobilization in vivo, suggesting a link between the GABA A R and anesthesia (5, 6). The expression of receptors containing chimeric subunits combining sequences from subunits conferring different anesthetic sensitivities led to the identification of two residues that determine the sensitivity of the GABA A R to volatile agents and alcohols (7). These residue...

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The Effects of Isoflurane on Desensitized Wild-Type and ??1(S270H) ??-Aminobutyric Acid Type A Receptors

Cited by 21 publications

References 24 publications

Synaptic-Type α1β2γ2L GABA_A Receptors Produce Large Persistent Currents in the Presence of Ambient GABA and Anesthetic Drugs

Synaptic-Type α1β2γ2L GABA_A Receptors Produce Large Persistent Currents in the Presence of Ambient GABA and Anesthetic Drugs

Response to neonatal anesthesia: Effect of sex on anatomical and behavioral outcome

Numerous Classes of General Anesthetics Inhibit Etomidate Binding to γ-Aminobutyric Acid Type A (GABAA) Receptors

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The Effects of Isoflurane on Desensitized Wild-Type and ??1(S270H) ??-Aminobutyric Acid Type A Receptors

Cited by 21 publications

References 24 publications

Synaptic-Type α1β2γ2L GABAA Receptors Produce Large Persistent Currents in the Presence of Ambient GABA and Anesthetic Drugs

Synaptic-Type α1β2γ2L GABAA Receptors Produce Large Persistent Currents in the Presence of Ambient GABA and Anesthetic Drugs

Response to neonatal anesthesia: Effect of sex on anatomical and behavioral outcome

Numerous Classes of General Anesthetics Inhibit Etomidate Binding to γ-Aminobutyric Acid Type A (GABAA) Receptors

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Product

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Synaptic-Type α1β2γ2L GABA_A Receptors Produce Large Persistent Currents in the Presence of Ambient GABA and Anesthetic Drugs

Synaptic-Type α1β2γ2L GABA_A Receptors Produce Large Persistent Currents in the Presence of Ambient GABA and Anesthetic Drugs