Sites of alcohol and volatile anaesthetic action on GABAA and glycine receptors

Mihic, S. John; Ye, Qing; Wick, Marilee J.; Koltchine, Vladimir V.; Krasowski, Matthew D.; Finn, Suzanne E.; Mascia, Maria Paola; Valenzuela, C. Fernando; Hanson, Kirsten K.; Greenblatt, Eric P.; Harris, R. Adron; Harrison, Neil L.

doi:10.1038/38738

Cited by 1,162 publications

(1,054 citation statements)

References 18 publications

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“…Position 15′ of the 5-HT 3A receptors TM2 domain is a non-pore-facing amino acid residue (Reeves et al, 2001;Panicker et al, 2002). In addition to its role in channel gating, the amino acid residue at 15′ also appears to have important roles in channel modulation by alcohol and anesthetics (Mihic et al, 1997;Wick et al, 1998), and binding of these drugs to a hydrophobic pocket involving this residue alters receptor function. In a separate study, we have demonstrated that L293 is critical for alcohol actions on the 5-HT 3A receptor; and L293C and L293S mutations abolish alcohol modulation (Hu et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…2A. Residue L293 is in the same 15′ position as a residue in the GABA A receptor that has important roles in channel gating (Findlay et al, 2001;Scheller & Forman, 2002) and modulation by alcohols and general anesthetics (Mihic et al, 1997;Wick et al, 1998). This amino acid residue is thought to reside on the non-porefacing side of TM2 domain (Panicker et al, 2002;Reeves et al, 2001).…”

Section: Role Of L293 In the Modulatory Action Of 5-himentioning

confidence: 99%

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The L293 residue in transmembrane domain 2 of the 5-HT3A receptor is a molecular determinant of allosteric modulation by 5-hydroxyindole

Lovinger

2008

Neuropharmacology

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Allosteric modulation of ligand-gated ion channels can play important roles in shaping synaptic transmission. The function of the 5-hydroxytryptamine (serotonin) type 3 (5-HT 3 ) receptor, a member of the Cys-loop ligand-gated ion channel superfamily, is modulated by a variety of compounds such as alcohols, anesthetics and 5-hydroxyindole (5-HI). In the present study, the molecular determinants of allosteric modulation by 5-HI were explored in N1E-115 neuroblastoma cells expressing the native 5-HT 3 receptor and HEK 293 cells transfected with the recombinant 5-HT 3A receptor using molecular biology and whole-cell patch-clamp techniques. 5-HI potentiated 5-HT-activated currents in both N1E-115 cells and HEK 293 cells, and significantly decreased current desensitization and deactivation. Substitution of Leu293 (L293, L15′) in the second transmembrane domain (TM2) with cysteine (L293C) or serine (L293S) abolished 5-HI modulation. Other mutations in the TM2 domain, such as D298A and T284F, failed to alter 5-HI modulation. The L293S mutation enhanced dopamine efficacy and converted 5-HI into a partial agonist at the mutant receptor. These data suggest that 5-HI stabilizes the 5-HT 3A receptor in the open state by decreasing both desensitization and 5-HT unbinding/channel closing; and L293 is a common site for both channel gating and allosteric modulation by 5-HI. Our observations also indicate existence of a second 5-HI recognition site on the 5-HT 3A receptor which may overlap with the 5-HT binding site and is not involved in the positive modulation by 5-HI. These findings support the idea that there are two discrete sites for 5-HI allosteric modulation and direct activation in the 5-HT 3A receptor.

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Section: Discussionmentioning

confidence: 99%

Section: Role Of L293 In the Modulatory Action Of 5-himentioning

confidence: 99%

The L293 residue in transmembrane domain 2 of the 5-HT3A receptor is a molecular determinant of allosteric modulation by 5-hydroxyindole

Lovinger

2008

Neuropharmacology

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“…A recent study suggests that neuroactive steroids contribute to the hypnotic effects of ethanol in rats (Khisti et al, 2003). Moreover, several studies (Mihic et al, 1997;Koltchine et al, 1999;Mascia et al, 2000;Ueno et al, 2001) have suggested that general anesthesia can be produced, at least in part, by enhancing neuronal inhibition mediated by the GABA A a-2 subunit.…”

Section: Subjective Effects Of Alcoholmentioning

confidence: 99%

GABRA2 Alleles Moderate the Subjective Effects of Alcohol, Which are Attenuated by Finasteride

Pierucci‐Lagha

Covault

Feinn

et al. 2005

Neuropsychopharmacol

133

109

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GABA A receptors are involved in the subjective effects of alcohol. Endogenous neuroactive steroids interact with GABA A receptors to mediate several behavioral effects of alcohol in rodents. Based on a haplotypic association of alcohol dependence with the gene encoding the GABA A receptor a-2 subunit (GABRA2), we examined whether GABRA2 alleles are associated with the subjective response to alcohol. We also examined whether finasteride (a 5-a steroid reductase inhibitor), which blocks the synthesis of some neuroactive steroids, reduces the subjective response to alcohol. In all, 27 healthy social drinkers (15 males) completed a randomized, double-blind, placebo-controlled study of high-dose finasteride. After being pretreated with study drug, subjects consumed three alcoholic drinks. Subjective effects were measured repeatedly over the ascending blood alcohol curve. To examine the moderating role of genetic variation in GABRA2, a single-nucleotide polymorphism that was informative in association studies was included as a factor in the analysis. Subjects homozygous for the more common A-allele (n ¼ 7) showed more subjective effects of alcohol than did individuals with one or two copies of the alcohol dependence-associated G-allele (n ¼ 20, including two homozygotes). Among the A-allele homozygotes, there was a greater reduction in several subjective effects during the finasteride session compared to the placebo session. These findings provide preliminary evidence that the risk of alcoholism associated with GABRA2 alleles may be related to differences in the subjective response to alcohol. The effects of finasteride provide indirect evidence for a mediating role of neuroactive steroids in some of the subjective effects of alcohol.

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“…This is in accordance with the suppression theory. Mihic et al (1997) have by clever use of chimeric constructs localized the binding sites for volatile anesthetics on the GABA channel. But what about the generality of this mechanism?…”

Section: Microscopic Effectsfmodulating Activity Of Critical Ion Chanmentioning

confidence: 99%

Mechanisms of Anesthesia: Towards Integrating Network, Cellular, and Molecular Level Modeling

Århem

Klement

Nilsson

2003

Neuropsychopharmacol

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The mechanisms of anesthesia are surprisingly little understood. The present article summarizes current knowledge about the function of general anesthetics at different organization levels of the nervous system. It argues that a consensus view can be constructed, assuming that general anesthetics modulate the activity of ion channels, the main targets being GABA and NMDA channels and possibly voltagegated and background channels, thereby hyperpolarizing neurons in thalamocortical loops, which lead to disruption of coherent oscillatory activity in the cortex. Two computational cases are used to illustrate the possible importance of molecular level effects on cellular level activity. Subtle differences in the mechanism of ion channel block can be shown to cause considerable differences in the modification of the oscillatory activity in a single neuron, and consequently in an associated network. Finally, the relation between the anesthesia problem and the classical consciousness problem is discussed, and some consequences of introducing the phenomenon of degeneracy into the picture are pointed out.

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Sites of alcohol and volatile anaesthetic action on GABAA and glycine receptors

Cited by 1,162 publications

References 18 publications

The L293 residue in transmembrane domain 2 of the 5-HT3A receptor is a molecular determinant of allosteric modulation by 5-hydroxyindole

The L293 residue in transmembrane domain 2 of the 5-HT3A receptor is a molecular determinant of allosteric modulation by 5-hydroxyindole

GABRA2 Alleles Moderate the Subjective Effects of Alcohol, Which are Attenuated by Finasteride

Mechanisms of Anesthesia: Towards Integrating Network, Cellular, and Molecular Level Modeling

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