Acute alcohol action and desensitization of ligand-gated ion channels

Alejandro Dopico, David M. Lovinger

Research output: Contribution to journalReview article

67 Citations (Scopus)

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 iono- tropic 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 α-amino-3- hydroxy5-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.

Original languageEnglish (US)
Pages (from-to)98-114
Number of pages17
JournalPharmacological Reviews
Volume61
Issue number1
DOIs
StatePublished - Mar 1 2009

Fingerprint

Ligand-Gated Ion Channels
Ethanol
Alcohols
Ion Channels
Biochemical Phenomena
Ligands
Protein Conformation
Proteins
Post Translational Protein Processing
Mutagenesis
gamma-Aminobutyric Acid
Alcoholism
Acetylcholine
Serotonin

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

Acute alcohol action and desensitization of ligand-gated ion channels. / Dopico, Alejandro; Lovinger, David M.

In: Pharmacological Reviews, Vol. 61, No. 1, 01.03.2009, p. 98-114.

Research output: Contribution to journalReview article

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