Anesthetic and ethanol effects on spontaneously opening glycine receptor channels.
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 alpha1 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 alpha1 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.
D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D019943:Amino Acid Substitution; D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D002725:Chloroform / Q000494:pharmacology; D004737:Enflurane / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology*; D005998:Glycine / Q000494:pharmacology; D018684:Glycine Agents / Q000494:pharmacology; D006801:Humans; D008845:Microinjections; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010852:Picrotoxin / Q000494:pharmacology; D018009:Receptors, Glycine / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013331:Strychnine / Q000494:pharmacology; D014982:Xenopus laevis
D000777:Anesthetics; D002725:Chloroform; D004737:Enflurane; D000431:Ethanol; D005998:Glycine; D018684:Glycine Agents; D010852:Picrotoxin; D018009:Receptors, Glycine; D013331:Strychnine