The Journal of Neurophysiology Vol. 78 No. 2 August 1997, pp. 582-590
Copyright ©1997 The American Physiological Society

Potentiation of NMDA Receptor-Mediated Responses by Dynorphin at Low Extracellular Glycine Concentrations

Li Zhang, Robert W. Peoples, Murat Oz, Judith Harvey-White, Forrest F. Weight, and Ulrike Brauneis

Laboratory of Molecular and Cellular Neurobiology, National Institute on Alcohol Abuse and Alcoholism, and Clinical Neuroscience Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892

Zhang, Li, Robert W. Peoples, Murat Oz, Judith Harvey-White, Forrest F. Weight, and Ulrike Brauneis. Potentiation of NMDA receptor-mediated responses by dynorphin at low extracellular glycine concentrations. J. Neurophysiol. 78: 582-590, 1997. The effect of dynorphin A(1-13) on N-methyl-D-aspartate (NMDA)-activated currents was investigated in the presence of low extracellular glycine concentrations in Xenopus oocytes expressing recombinant heteromeric NMDA receptors and in cultured hippocampal neurons with the use of voltage-clamp techniques. At an extracellular added glycine concentration of 100 nM, dynorphin A(1-13) (10 µM) greatly increased the amplitude of NMDA-activated currents for all heteromeric subunit combinations tested; on average, the potentiation was: 1/1, 3,377 ± 1,416% (mean ± SE); 2/1, 1,897 ± 893%; 3/1, 4,356 ± 846%; and 4/1, 1,783 ± 503%. Potentiation of NMDA-activated current by dynorphin A(1-13) was concentration dependent between 0.1 and 10 µM dynorphin A(1-13), with a half-maximal concentration value of 2.77 µM and an apparent Hill coefficient of 2.53, for 2/1 subunits at 100 nM added extracellular glycine. Percentage potentiation by dynorphin A(1-13) was maximal at the lowest glycine concentrations tested (0.01 and 0.1 µM), and decreased with increasing glycine concentration. No significant potentiation was observed at glycine concentrations >0.1 µM for 1/1, 2/1, and 4/1 subunits, or at >1 µM for 3/1 subunits. Potentiation of NMDA-activated currents by dynorphin A(1-13) was not inhibited by 1 µM of the -opioid receptor antagonist nor-binaltorphimine, and potentiation was not observed with 10 µM of the -opioid receptor agonist trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzene-acetamide. Potentiation of NMDA-activated current by dynorphin A(1-13) was inhibited by the glycine antagonist kynurenic acid (50 µM). NMDA-activated current was also potentiated at low glycine concentrations by 10 µM dynorphin A(2-13) or (3-13), both of which have a glycine as the first amino acid, but not by 10 µM dynorphin A(4-13), which does not have glycine as an amino acid. In hippocampal neurons, 10 µM dynorphin A(1-13) or (2-13) potentiated steady-state NMDA-activated current in the absence of added extracellular glycine. The extracellular free glycine concentration, determined by high-performance liquid chromatography, was between 26 and 36 nM for the bathing solution in presence or absence of 10 µM dynorphin A(1-13), (2-13), (3-13), or (4-13), and did not differ significantly among these solutions. The observations are consistent with the potentiation of NMDA-activated current at low extracellular glycine concentrations resulting from an interaction of the glycine amino acids in dynorphin A(1-13) with the glycine coagonist site on the NMDA receptor. Because dynorphin A is an endogenous peptide that can be coreleased with glutamate at glutamatergic synapses, the potentiation of NMDA receptor-mediated responses could be an important physiological regulator of NMDA receptor function at these synapses.

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