Acute alcohol action and desensitization of ligand-gated ion channels

Abstract

Ethanol exerts its biological actions through multiple receptors, including ion channels. Ion channels that are sensitive to pharmacologically relevant ethanol concentrations constitute a heterogeneous set, including structurally unrelated proteins solely sharing the property that their gating is regulated by a ligand(s). Receptor desensitization is almost universal among these channels, and its modulation by ethanol may be a crucial aspect of alcohol pharmacology and effects in the body. We review the evidence documenting interactions between ethanol and ionotropic receptor desensitization, and the contribution of this interaction to overall ethanol action on channel function. In some cases, such as type 3 serotonin, nicotinic acetylcholine, GABA-A, and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors, ethanol actions on apparent desensitization play a significant role in acute drug action on receptor function. In a few cases, mutagenesis helped to identify different areas within a receptor protein that differentially sense n-alcohols, resulting in differential modulation of receptor desensitization. However, desensitization of a receptor is linked to a variety of biochemical processes that may alter protein conformation, such as the lipid microenvironment, post-translational channel modification, and channel subunit composition, the relative contribution of these processes to ethanol interactions with channel desensitization remains unclear. Understanding interactions between ethanol and ionotropic receptor desensitization may help to explain different ethanol actions 1) when ethanol is evaluated in vitro on cloned channel proteins, 2) under physiological or pathological conditions or in distinct cell domains with modified ligand concentration and/or receptor conformation. Finally, receptor desensitization is likely to participate in molecular and, possibly, behavioral tolerance to ethanol, which is thought to contribute to the risk of alcoholism.

Fig. 1.

A general kinetic scheme for the gating of the 5-HT₃ ligand-gated ion channel. Transitions between channel states are governed by rate constants denoted above and below the arrows. Although the main pathway governing desensitization is expected to occur at full occupancy of the receptor by the ligand (A₃O↔ A₃D), entry into desensitized states may occur from partially ligated channel states (A₂O, A₁O) and even the unligated, open channel receptor; r = receptor, A = agonist, O = open channel state(s), D = desensitized state(s). [Adapted from Hu XQ and Lovinger DM (2008) The L293 residue in transmembrane domain 2 of the 5-HT3A receptor is a molecular determinant of allosteric modulation by 5-hydroxyindole. Neuropharmacology 54:1153–1165. Copyright © 2008 Elsevier, Ltd. Used with permission.]

Fig. 2.

Simple, empirically derived kinetic models showing that ethanol modulation of Ca²⁺_i-dependent channel dwelling into a low activity (P_o) mode is a major determinant of the final drug action on BK channel activity. At high concentrations of activating ligand (Ca²⁺_i), channel activity could be satisfactorily modeled only by introducing an additional component corresponding to the Ca²⁺_i-driven low-activity mode (C versus A), which can be interpreted as a set of channel desensitized states. At low ligand concentrations, ethanol prevents channel entry into long-closed states by increasing the C3→C2 transition and decreasing O3→C3. In addition, ethanol stabilizes openings within the normal-activity mode by shifting the O2↔ C2 equilibrium toward O2 (B versus A). These kinetic changes explain ethanol-induced potentiation of BK P_o at low ligand concentrations, as widely reported (Brodie et al., 2007). At high activating ligand concentrations, however, ethanol mildly diminishes the C3→C2 transition and drastically shifts the C3↔ low activity mode equilibrium toward the latter (5 times) (D versus C), favoring channel dwelling within the low-activity mode. These kinetic changes explain ethanol-induced reduction of BK P_o at high activating ligand concentrations (Liu et al., 2008). Main changes introduced by ethanol and/or increase in internal calcium are bolded. [Adapted from Liu J, Vaithianathan T, Manivannan K, Parrill A, and Dopico AM (2008) Ethanol modulates BK_Ca channels by acting as an adjuvant of calcium. Mol Pharmacol 74:628–640. Copyright © 2008 American Society for Pharmacology and Experimental Therapeutics.