Differential sensitivity of recombinant N-methyl-D-aspartate receptor subunits to inhibition by dynorphin.
Dynorphin is an endogenous ligand for kappa-opioid receptors. We investigated the effect of dynorphin 1-13 on different heteromeric subunits of recombinant mouse N-methyl-D-aspartate (NMDA) receptors expressed in Xenopus oocytes by using voltage-clamp recording methods. Dynorphin inhibited the NMDA-activated currents of all heteromeric NMDA receptor subunits tested. The different NMDA receptor subunits, however, exhibited a differential sensitivity to dynorphin. For the epsilon-1/zeta-1 subunit combination the EC50 was 19 microM; the other NMDA receptor subunit combinations were less sensitive to dynorphin and had the following order of sensitivity: epsilon-2/zeta-1 > epsilon-4/zeta-1 > epsilon-3/zeta-1. Inhibition of NMDA-activated currents by dynorphin was not competitive with NMDA, and was voltage-independent. NMDA-activated currents were not affected by the synthetic kappa-opioid receptor agonist U50488 ¿trans-3, 4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzene-acetamide¿, the specific kappa-opioid receptor antagonist nor-binaltorphimine1 or the nonspecific opioid receptor antagonist naloxone. In addition, nor-binaltorphimine1 or naloxone did not attenuate dynorphin inhibition of NMDA-activated current. The observations suggest that dynorphin inhibition of NMDA receptor function is mediated by an interaction of dynorphin with NMDA receptors, rather than an action involving kappa-opioid receptors. The data also show that different heteromeric NMDA receptor subunits exhibit a differential sensitivity to dynorphin.
Brauneis
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Laboratory of Molecular and Cellular Neurobiology, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA.
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Peoples
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Zhang
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D000818:Animals; D004305:Dose-Response Relationship, Drug; D004399:Dynorphins / Q000494:pharmacology*; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D016202:N-Methylaspartate / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000037:antagonists & inhibitors*; D017473:Receptors, Opioid, kappa / Q000819:agonists; D011994:Recombinant Proteins / Q000819:agonists / Q000037:antagonists & inhibitors; D014981:Xenopus
D016194:Receptors, N-Methyl-D-Aspartate; D017473:Receptors, Opioid, kappa; D011994:Recombinant Proteins; D016202:N-Methylaspartate; D004399:Dynorphins