Voltage-dependent inhibition of recombinant NMDA receptor-mediated currents by 5-hydroxytryptamine.
The effect of 5-HT and related indolealkylamines on heteromeric recombinant NMDA receptors expressed in Xenopus oocytes was investigated using the two-electrode voltage-clamp recording technique. In the absence of external Mg(2+) ions, 5-HT inhibited NMDA receptor-mediated currents in a concentration-dependent manner. The inhibitory effect of 5-HT was independent of the NR1a and NR2 subunit combination. The inhibition of glutamate-evoked currents by 5-HT was use- and voltage-dependent. The voltage sensitivity of inhibition for NR1a+NR2 subunit combinations by 5-HT was similar, exhibiting an e-fold change per approximately 20 mV, indicating that 5-HT binds to a site deep within the membrane electric field. The inhibition of the open NMDA receptor by external Mg(2+) and 5-HT was not additive, suggesting competition between Mg(2+) and 5-HT for a binding site in the NMDA receptor channel. The concentration-dependence curves for 5-HT and 5-methoxytryptamine (5-MeOT) inhibition of NMDA receptor-mediated currents are shifted to the right in the presence of external Mg(2+). The related indolealkylamines inhibited glutamate-evoked currents with the following order of inhibitory potency: 5-MeOT=5-methyltryptamine>tryptamine>7-methyltryptamine>5-HT>>tryptophan=melatonin. Taken together, these data suggest that 5-HT and related compounds can attenuate glutamate-mediated excitatory synaptic responses and may provide a basis for drug treatment of excitoxic neurodegeneration.
Kloda
Anna
A
School of Biomedical Sciences, University of Queensland, Brisbane, Queensland 4072, Australia.
Adams
David J
DJ
D000465:Algorithms; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D007473:Ion Channels / Q000187:drug effects; D007700:Kinetics; D008274:Magnesium / Q000494:pharmacology; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins; D012701:Serotonin / Q000494:pharmacology*; D014981:Xenopus
D018691:Excitatory Amino Acid Antagonists; D007473:Ion Channels; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins; D012701:Serotonin; D012313:RNA; D008274:Magnesium