Dynorphin A inhibits NMDA receptors through a pH-dependent mechanism.
Dynorphin A (DynA), an endogenous agonist of kappa-opioid receptors, has also been reported to directly interact with the NMDA receptor. DynA inhibition of NMDA receptor function has been suggested to be involved in its neuroprotective action during ischemic and acidic conditions. However, the effect of external pH on DynA inhibition of the NMDA receptor has not been reported. Here, we show that DynA inhibition of the NMDA receptor is dependent on extracellular pH over the range of pH 6.7-8.3, and the inhibition by 10 microM DynA increases at low pH by three- to four-fold in hippocampal neurons and in Xenopus oocytes expressing NR1-1a/2B subunits. Molecular studies showed that the interacting site for DynA on the NMDA receptor is distinct from that of proton or redox sites. Peptide mapping demonstrated important contributions of positively charged residues and specific structural organization of the peptide to the potency of DynA inhibition. Thus, DynA inhibits NMDA receptors through an allosteric mechanism, which is pH dependent and involves the specific structural features of the peptide.
Kanemitsu
Yoshio
Y
Laboratory of Molecular and Cellular Neurobiology, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892-8115, USA.
Hosoi
Masako
M
Zhu
Ping Jun
PJ
Weight
Forrest F
FF
Peoples
Robert W
RW
McLaughlin
Joseph S
JS
Zhang
Li
L
D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002460:Cell Line; D004399:Dynorphins / Q000378:metabolism* / Q000494:pharmacology; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009865:Oocytes; D009924:Organ Culture Techniques; D010084:Oxidation-Reduction / Q000187:drug effects; D018408:Patch-Clamp Techniques; D017434:Protein Structure, Tertiary / Q000502:physiology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D014982:Xenopus laevis
C409466:NR1 NMDA receptor; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D004399:Dynorphins