Sites of volatile anesthetic action on kainate (Glutamate receptor 6) receptors.
Department of Pharmacology, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA. Journal of Biological Chemistry
(Impact Factor: 4.57).
Molecular mechanisms of anesthetic action on neurotransmitter receptors are poorly understood. The major excitatory neurotransmitter in the central nervous system is glutamate, and recent studies found that volatile anesthetics inhibit the function of the alpha-amino-3-hydroxyisoxazolepropionic acid subtype of glutamate receptors (e.g. glutamate receptor 3 (GluR3)), but enhance kainate (GluR6) receptor function. We used this dissimilar pharmacology to identify sites of anesthetic action on the kainate GluR6 receptor by constructing chimeric GluR3/GluR6 receptors. Results with chimeric receptors implicated a transmembrane region (TM4) of GluR6 in the action of halothane. Site-directed mutagenesis subsequently showed that a specific amino acid, glycine 819 in TM4, is important for enhancement of receptor function by halothane (0. 2-2 mM). Mutations of Gly-819 also markedly decreased the response to isoflurane (0.2-2 mM), enflurane (0.2-2 mM), and 1-chloro-1,2, 2-trifluorocyclobutane (0.2-2 mM). The nonanesthetics 1, 2-dichlorohexafluorocyclobutane and 2,3-dichlorooctafluorobutane had no effect on the functions of either wild-type GluR6 or receptors mutated at Gly-819. Ethanol and pentobarbital inhibited the function of both wild-type and mutant receptors. These results suggest that a specific amino acid, Gly-819, is critical for the action of volatile anesthetics, but not of ethanol or pentobarbital, on the GluR6 receptor.
Available from: Romain Nardou
- "Several studies have shown earlier that PB (and pentobarbital) reduced glutamatergic AMPA/kainate receptor mediated currents including: (i) a subunit selective action on kainate-induced currents in Xenopus oocytes expressing different GluR subunits (DildyMayfield et al., 1996; Minami et al., 1998); (ii) a reduction of glutamate currents in spinal cord neurons (Barker and Gainer, 1973; MacDonald and Barker, 1978b; Taverna et al., 1994; Joo et al., 1999). PB – like DZP (Rovira and Ben-Ari, 1994) – also reduced calcium currents (Werz and Macdonald, 1985). "
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Frontiers in Cellular Neuroscience 07/2011; 5:16. DOI:10.3389/fncel.2011.00016 · 4.29 Impact Factor
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