Anesthetic and ethanol effects on spontaneously opening glycine receptor channels

• Published in: Journal of neurochemistry 2002-09, Vol.82 (6), p.1343-1351
• Main Authors: Beckstead, Michael J., Phelan, Rachel, Trudell, James R., Bianchini, Michael J., Mihic, S. John
• Format: Article
• Language: English
• Subjects: Allosteric Regulation - drug effects; Allosteric Regulation - physiology; Amino Acid Substitution; Aminoacid receptors (glycine, glutamate, gaba); Anesthetics - pharmacology; Animals; Biological and medical sciences; Biological Transport - drug effects; Biological Transport - physiology; Cell receptors; Cell structures and functions; Chloroform - pharmacology; constitutive activity; efficacy; Enflurane - pharmacology; ethanol; Ethanol - pharmacology; Fundamental and applied biological sciences. Psychology; Glycine - pharmacology; Glycine Agents - pharmacology; glycine receptor; Humans; inhaled drugs of abuse; Microinjections; Models, Molecular; Molecular and cellular biology; Mutagenesis, Site-Directed; Oocytes - drug effects; Oocytes - metabolism; Patch-Clamp Techniques; Picrotoxin - pharmacology; Receptors, Glycine - drug effects; Receptors, Glycine - genetics; Receptors, Glycine - metabolism; Structure-Activity Relationship; Strychnine - pharmacology; volatile anesthetic; Xenopus laevis
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1046/j.1471-4159.2002.01086.x

Strychnine‐sensitive glycine receptors mediate inhibitory neurotransmission occurring in the brain stem and spinal cord. Alcohols, volatile anesthetics and inhaled drugs of abuse are positive allosteric modulators of glycine receptor function, normally enhancing function only in the presence of glycine. A complication in studying allosteric actions on ligand‐gated ion channels is in the dissection of their effects on neurotransmitter binding from their effects on channel opening. Mutation of an aspartate residue at position 97 to arginine in the glycine receptor α1 subunit simulated the effects of glycine binding, producing receptors that exhibited tonic channel opening in the absence of neurotransmitter; i.e. these receptors demonstrated a dissociation of channel opening from neurotransmitter binding. In these receptors, ethanol, enflurane, chloroform, halothane, 1,1,1‐trichloroethane and toluene elicited inward currents in the absence of glycine. We previously identified mutations on ligand‐gated ion channels that eliminate ethanol, anesthetic and inhalant actions (such as S267I on α1 glycine receptors). The double mutant (D97R and S267I) receptors were both constitutively active and resistant to the enhancing effects of ethanol and enflurane. These data demonstrate that ethanol and volatile anesthetics can affect glycine receptor channel opening independently of their effects on enhancing neurotransmitter binding.