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Journal of Neuroscience, Vol 15, 3162-3171, Copyright © 1995 by Society for Neuroscience
Ethanol inhibits kainate responses of glutamate receptors expressed in Xenopus oocytes: role of calcium and protein kinase C
JE Dildy-Mayfield and RA Harris
Department of Pharmacology, University of Colorado Health Sciences Center, Denver 80262, USA.
Recombinant alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid
(AMPA)/kainate receptors expressed in oocytes are inhibited by ethanol and
the sensitivity to ethanol depends on the kainate concentration and the
subunit(s) expressed. For example, GluR3 kainate channels are more
sensitive to inhibition by ethanol than GluR6 channels in the presence of
maximally effective kainate concentrations. To determine if the ethanol
inhibition was influenced by the cation permeability (Na+ vs Na+ and Ca2+)
of the channels expressed, we compared ethanol inhibition of
Ca(2+)-permeable glutamate receptors (GluRs) in oocytes perfused with
normal- and high-Ca2+ buffers. The ethanol inhibition was much greater when
Ca2+ was the only permeant cation. When Ba2+ was substituted for Ca2+, the
ethanol inhibition was reduced, although it was still greater than with
normal buffer. The enhanced ethanol inhibition of kainate-stimulated Ca2+
currents was reduced in oocytes injected with the Ca2+ chelator BAPTA,
suggesting a role for intracellular Ca2+ in mediating enhanced ethanol
sensitivity of kainate channels. The enhanced ethanol inhibition of Ca2+
currents was not due to a direct ethanol inhibition of Ca(2+)-stimulated
Cl- currents in the oocyte because ethanol produced no effect on
Ca(2+)-stimulated Cl- currents induced by injection of
myo-inositol-1,4,5-trisphosphate. Because Ca2+ activates protein kinase C
(PKC) and because we found that the PKC activator phorbol 12-myristate
13-acetate inhibits kainate responses (Dildy-Mayfield and Harris, 1994), we
examined the role of PKC in mediating the enhanced ethanol inhibition of
kainate responses produced by increased Ca2+. Inhibition of PKC by
injection of the PKC inhibitor peptide or calphostin C prevented the
enhanced ethanol inhibition of kainate-induced Ca2+ responses without
altering ethanol inhibition in normal buffer. Thus, ethanol inhibition of
kainate channels may involve two mechanisms, one that is independent of PKC
and a second type that is due to activation of PKC under conditions of
elevated Ca2+, resulting in enhanced inhibition of kainate responses.
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