Ethanol modulation of LGIC desensitization and its contribution to drug effect on channel activity
| Desensitization Impact on Overall Kinetics | Ethanol Modulation of Desensitization | Ethanol Effect on Overall Channel Activity | |
|---|---|---|---|
| Ionotropic receptors gated by extracellular ligands | |||
| The cys-loop family | |||
| 5-HT3 | Desensitization is slow (seconds) and a major determinant of overall deactivation | Variable: increase at subsaturating [agonist]; decrease at saturating [agonist] | Activates 5-HT3A, which declines as [agonist] increases; 5HT3B blunts ethanol potentiation |
| nAchR | Desensitization is complex, with fast and slow states. In general, current decay increases as [agonist] increases; desensitization is mainly dependent on channel subunit composition | In general, increase at subsaturating [agonist]. Ethanol action on desensitization might be dependent on cholesterol around the channel | Usually, activation at low [agonist]. Ethanol >250 mM may inhibit current because of stabilization of desensitized states |
| GABA-A | Fast and slow phases (milliseconds to several seconds) even in continuous presence of agonist. Several micromolar GABA render more than one desensitization component even in a single channel subtype | Undetermined for native channels and most recombinants. Increased desensitization of α6β2γ2S channels. No apparent effect in GABA-ARs with δ subunit | Variable, largely dependent on subunit composition and expression system. Consistent potentiation of recombinant channels expressed in X. laevis oocytes |
| Glycine | Slow. A fast component (τ≈5 ms) is seen with clustering of α1 or coexpression of β | Largely unexplored, but it seems not to be a major contributor of ethanol effects on gating | Potentiation of native and recombinant channels. Ethanol may decrease deactivation of current |
| Ionotropic receptors gated by glutamate | |||
| AMPA | Faster than that observed with kainate receptors | Decreased extent of steady-state desensitization. Decreased rate of exit from desensitized state induced by kainate | Inhibition, depending on agonist used and kinetic state |
| NMDA | Desensitization induced by NMDA in calcium presence. In addition, separate desensitization by either aspartate or glycine | Stabilization of desensitized state(s) | Inhibition, yet contribution of desensitization to this effect remains to be established |
| Kainate | Slower than that of AMPA | Undetermined | Inhibition |
| Ionotropic receptors gated by ATP | |||
| Desensitization in presence of continuous ATP varies with subunit composition and intracellular signaling | Formally untested, yet ethanol accelerates macroscopic current deactivation | Inhibition of native channels and most homomeric recombinants yet contribution of desensitization to drug action is unknown. | |
| K+ channels gated by intracellular ligands | |||
| BK | Channel enters a low activity mode at 10–1000 μM Ca2+ | At Ca2+ >10 μM, ethanol favors slo1 and slo1+β4 channel entry into low activity mode | Variable, depending on [agonist]. Channel entry into low-activity mode leads to inhibition |
| GIRK | Desensitization in a few minutes due to Gq protein downstream signaling | Undetermined | Potentiation. Unlikely that putative drug action on desensitization contributes to ethanol effect on current |