Editors' ChoicePharmacology

Putting Synapses to Sleep

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Science's STKE  23 Sep 2003:
Vol. 2003, Issue 201, pp. tw373
DOI: 10.1126/stke.2003.201.tw373

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]