Anesthetic-like modulation of a gamma-aminobutyric acid type A, strychnine-sensitive glycine, and N-methyl-d-aspartate receptors by coreleased neurotransmitters.
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.
Milutinovic
Pavle S
PS
University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Yang
Liya
L
Cantor
Robert S
RS
Eger
Edmond I
EI
Sonner
James M
JM
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
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