Modulation of nicotinic acetylcholine receptors by noncompetitive antagonists

Abstract

All members from the nicotinic acetylcholine receptor family are pentameric proteins bearing an intrinsic cation channel. The function of these ion channels can be modulated by structurally-different compounds called noncompetitive antagonists (NCAs), including exogenous compounds such as general and local anesthetics, quinacrine, and antidepressants, as well as endogenous molecules such as free fatty acids and neurosteroids. NCAs may act at least by two different mechanisms: a steric and/or an allosteric mechanism. The simplest idea representing a steric mechanism is that the NCA molecule physically blocks the ion channel. Instead, there exist distinct allosteric mechanisms. For example, NCAs may (a) bind to the nAChR, stabilizing a nonconducting conformational state (e.g., resting or desensitized state), and/or (b) increase the nAChR desensitization rate, decreasing subsequently the probability of channel opening. Barbiturates, dissociative anesthetics, quinacrine, antidepressants, fatty acids, and neurosteroids have been shown to inhibit nAChRs by allosteric mechanisms and/or by open- and closed-channel blockade. Consistent with its lipidic nature, fatty acids and neurosteroids preferably interact with the lipid-protein interface. These lipids as well as quinacrine seem to interact with the nonannular lipid domain, a special not very well defined lipid domain distinct to that sourrounding the receptor perimeter (i.e., the annular lipid domain). For most of the NCAs, modulation has proved to be highly complex. Some NCAs may act by more than one mechanism and their mechanisms of action may differ among nAChR subtypes. The actual knowledge on the structure of the nAChR, its NCA binding site locations, and the noncompetitive inhibition mechanisms will help to the design of new and more efficacious drugs for the treatment of different neurological diseases.