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-c-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 μM; 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.