RT Journal Article
SR Electronic
T1 Putting Synapses to Sleep
JF Science's STKE
JO Sci. STKE
FD American Association for the Advancement of Science
SP tw373
OP tw373
DO 10.1126/stke.2003.201.tw373
VO 2003
IS 201
YR 2003
UL http://stke.sciencemag.org/content/2003/201/tw373.abstract
AB Despite a century of clinical use, the mechanism by which the lipid-soluble inhalation anesthetics alter synaptic transmission remains unknown. Fang et al. show that halothane, isoflurane, and sevoflurane dose dependently inhibited the interaction between the synaptic scaffold PSD-95 and neuronal nitric oxide synthase (nNOS) and between PSD-95 and N-methyl-D-aspartate (NMDA) receptor subunits NR2A and NR2B. Inhalation anesthetics disrupted the interactions detected by yeast two-hybrid assays, glutathione-S-transferase pull-down assays, and coimmunoprecipitation assays. Surface plasmon resonance assays indicated that the affinity of the interactions was unchanged, but that fewer binding sites were available in the presence of halothane. (This effect was specific to inhalation anesthetics because ethanol did not alter binding.) Finally, nuclear magnetic resonance chemical shift perturbation analysis mapped the halothane binding site on the second PDZ domain of PSD-95 to the same hydrophobic groove that is the binding site for nNOS and the NMDA receptor. M. Fang, Y.-X. Tao, F. He, M. Zhang, C. F. Levine, P. Mao, F. Tao, C.-L. Chou, S. Sadegh-Nasseri, R. A. Johns, Synaptic PDZ domain-mediated protein interactions are disrupted by inhalational anesthetics. J. Biol. Chem. 278, 36669-36675 (2003). [Abstract] [Full Text]