title: Anesthetic-like modulation of a gamma-aminobutyric acid type A, strychnine-sensitive glycine, and N-methyl-d-aspartate receptors by coreleased neurotransmitters.
abstract: BACKGROUND
  A mechanism of anesthesia has recently been proposed which predicts that coreleased neurotransmitters may modulate neurotransmitter receptors for which they are not the native agonist in a manner similar to anesthetics.
  
  
  METHODS
  We tested this prediction by applying acetylcholine to a NR1/NR2A N-methyl-d-aspartate receptor, glycine to a wild-type alpha(1)beta(2) and anesthetic-resistant alpha(1)(S270I)beta(2) gamma-amino-butyric acid (GABA) type A receptor, and GABA to a homomeric alpha(1) wild type and anesthetic-resistant alpha(1) S267I glycine receptor. Receptors were expressed in Xenopus laevis oocytes and studied using two-electrode voltage clamping.
  
  
  RESULTS
  We found inhibition of N-methyl-d-aspartate receptor function by acetylcholine, enhancement of glycine receptor function by GABA, and enhancement of GABA type A receptor function by glycine. As expected of compounds with anesthetic activity, GABA showed far less potentiation (enhancement) of the function of the anesthetic-resistant S267I glycine receptor than that of the wild-type receptor. Glycine potentiated the function of wild-type GABA type A receptors but inhibited the function of the anesthetic-resistant S270I GABA type A receptor.
  
  
  CONCLUSIONS
  These results show that neurotransmitters that are coreleased onto anesthetic-sensitive receptors may modulate the function of receptors for which they are not the native agonist via an anesthetic-like mechanism. These findings lend support to a recent theory of anesthetic action.
authors.affiliation: University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Pavle S
authors.initials: PS
authors.lastname: Milutinovic
authors.forename: Liya
authors.initials: L
authors.lastname: Yang
authors.forename: Robert S
authors.initials: RS
authors.lastname: Cantor
authors.forename: Edmond I
authors.initials: EI
authors.lastname: Eger
authors.forename: James M
authors.initials: JM
authors.lastname: Sonner
mesh_terms: D000109:Acetylcholine / Q000378:metabolism / Q000494:pharmacology; D000777:Anesthetics / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D058785:GABA-A Receptor Agonists; D005998:Glycine / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D018377:Neurotransmitter Agents / Q000378:metabolism / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000502:physiology*; D018009:Receptors, Glycine / Q000819:agonists / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000502:physiology*; D013331:Strychnine; D014982:Xenopus laevis; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000777:Anesthetics; D058785:GABA-A Receptor Agonists; D018377:Neurotransmitter Agents; D011963:Receptors, GABA-A; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D005680:gamma-Aminobutyric Acid; D013331:Strychnine; D000109:Acetylcholine; D005998:Glycine