Results: 4

1.
Fig. 1.

Fig. 1. From: Ethanol enhances ?4?3? and ?6?3? ?-aminobutyric acid type A receptors at low concentrations known to affect humans.

Comparison of synaptic (αβγ) and extrasynaptic (αβδ) GABARs. (a) Comparison of GABAR currents expressed in Xenopus oocytes. GABARs composed of α4β2δ-subunits show a slower desensitization and are activated at much lower concentrations of GABA than those formed by α4β2γ2S.(b) GABA dose-responses on GABAR subunit combinations containing either α4- or α6-subunits, with β2- or β3-subunits, with and without γ2S-, γ2L-, or δ-subunits. The plots shown are for α6β3δ, α6β3γ2L, α1β3γ2L, α6β3γ2S, and α6β3. GABARs containing α4-in place of α6-, and β2-instead of β3-subunits are virtually identical (see Table 1 for EC50 values). The αβ-subunits produce small-current levels and have a fairly low potency for GABA (EC50 ≈ 22 μM GABA). γ-Subunit-containing receptors respond to lower concentrations of GABA (γ2S,EC50 ≈ 18 μM GABA; α1β3γ2L,EC50 ≈ 10 μM GABA; α6β3γ2L, ≈ 8 μM GABA). δ-containing receptors are the most GABA-sensitive with just-detectable responses evident at concentrations as low as 30 nM GABA (EC50 ≈ 0.57 μM GABA).

M. Wallner, et al. Proc Natl Acad Sci U S A. 2003 December 9;100(25):15218-15223.
2.
Fig. 2.

Fig. 2. From: Ethanol enhances ?4?3? and ?6?3? ?-aminobutyric acid type A receptors at low concentrations known to affect humans.

δ-Subunit-containing GABARs as targets for neuroactive steroids, the general anesthetic etomidate, and ethanol. (a) GABA dose-response curve of α4β2δ GABAR alone and in the presence of 1 μM THDOC shows an up to 5-fold increase in peak currents with 1 μM THDOC even at saturating GABA concentrations. (b) Dose-response curve of the general anesthetic etomidate on α6β3δ GABAR current. Etomidate was coapplied with almost saturating amounts of GABA (10 μM = EC95). (c) EtOH coapplication with 10 μM (EC95) GABA causes an increase in current levels in α6β3δ GABARs as low as 3 mM and triples the peak currents at 1 M. Shown are single traces with full dose-response curves that demonstrate that GABA is only a partial agonist at δ-subunit-containing receptors. Similar results have been obtained with application of selected concentrations of THDOC, etomidate, and EtOH and with other δ-subunit-containing GABARs. Peaks marked with “0” show current responses to 10 μM GABA without etomidate or EtOH. Application of 1 μM THDOC, 300 μM etomidate, or 1 M EtOH alone does not evoke significant currents in α6β3δ-expressing oocytes (not shown).

M. Wallner, et al. Proc Natl Acad Sci U S A. 2003 December 9;100(25):15218-15223.
3.
Fig. 3.

Fig. 3. From: Ethanol enhances ?4?3? and ?6?3? ?-aminobutyric acid type A receptors at low concentrations known to affect humans.

Both the β3- and δ-subunits are required for high ethanol sensitivity. (a) EtOH current enhancement when coapplied with respective EC20 values of the various subunit combinations. αβδ-Subunits show the largest enhancement, β3-containing receptors being the most sensitive. γ-containing GABAR currents show significant potentiation only at 100 mM EtOH, and αβ-subunits seem to be completely insensitive. The plots shown are for α6β3δ (♦), α4β3δ (○), α4β2δ (×), α6β3γ2L (▴), α6β3γ2S (▿), and α6β3 (▪) (n = 13, 12, 15, 10, 9, and 5, respectively); the remaining combinations with δ, γ2S, or γ2L or neither were virtually indistinguishable from the subunits represented (see Table 2 for pooled EtOH-response values). (b) EtOH effects on tonically activated receptors. Replacement of β2-with β3-subunits in α4βδ or α6βδ GABARs leads to an almost 10-fold increase in EtOH sensitivity. EtOH response (from 3 to 300 mM) on α4β2δ-, α4β3δ-, α6β2δ-, and α6β3δ-containing GABARs activated by steady-state 300 nM GABA (≈EC30).

M. Wallner, et al. Proc Natl Acad Sci U S A. 2003 December 9;100(25):15218-15223.
4.
Fig. 4.

Fig. 4. From: Ethanol enhances ?4?3? and ?6?3? ?-aminobutyric acid type A receptors at low concentrations known to affect humans.

Synaptic versus extrasynaptic receptors. Synaptic receptors (shown is the most prevalent α1β2γ2 synaptic GABARs) respond to saturating GABA (>1 mM peak GABA concentrations) and show high efficacy but fairly low potency (45). In contrast, extrasynaptic receptors (composed of α4δ- or α6δ- and most likely β3-subunits) are activated by persistent and usually nonsaturating ambient GABA concentrations (0.5-1 μM), and, even at saturating GABA concentrations, are characterized by low-current levels (high-potency, low-efficacy receptors). We suggest a model where EtOH and other anesthetics lead to an increase in GABA efficacy (increase in open probability and/or possibly single-channel conductance), which leads to increased Cl- current. A massive increase in GABA-activated Cl- conductance by anesthetics could completely silence neurons expressing δ-subunit-containing GABARs, thereby producing anesthesia. The activation of extrasynaptic GABARs is functionally equivalent to activation of background K+ channels. G protein-coupled inwardly rectifying K+ (GIRK) channels have been shown to respond to fairly low concentrations of EtOH (3, 4) and may mediate EtOH analgesic actions (5). GIRK channels may also contribute to the anesthetic actions of volatile anesthetics (48, 49). The two-pore K+ channels, TASK1 and TREK, are likely targets for volatile anesthetics (35, 36, 50, 51). The functional similarity between extrasynaptic GABARs and two-pore K+ channels is supported by the finding that, in cerebellar granule cells, a background potassium channel (most likely TASK1), compensates for the loss of extrasynaptic GABARs in mice lacking the GABAR α6-subunit (37).

M. Wallner, et al. Proc Natl Acad Sci U S A. 2003 December 9;100(25):15218-15223.

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