Novel dimeric bis(7)-tacrine proton-dependently inhibits NMDA-activated currents.
Bis(7)-tacrine has been shown to prevent glutamate-induced neuronal apoptosis by blocking NMDA receptors. However, the characteristics of the inhibition have not been fully elucidated. In this study, we further characterize the features of bis(7)-tacrine inhibition of NMDA-activated current in cultured rat hippocampal neurons. The results show that with the increase of extracellular pH, the inhibitory effect decreases dramatically. At pH 8.0, the concentration-response curve of bis(7)-tacrine is shifted rightwards with the IC(50) value increased from 0.19+/-0.03 microM to 0.41+/-0.04 microM. In addition, bis(7)-tacrine shifts the proton inhibition curve rightwards. Furthermore, the inhibitory effect of bis(7)-tacrine is not altered by the presence of the NMDA receptor proton sensor shield spermidine. These results indicate that bis(7)-tacrine inhibits NMDA-activated current in a pH-dependent manner by sensitizing NMDA receptors to proton inhibition, rendering it potentially beneficial therapeutic effects under acidic conditions associated with stroke and ischemia.
Luo
Jialie
J
Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, PR China.
Li
Wenming
W
Liu
Yuwei
Y
Zhang
Wei
W
Fu
Hongjun
H
Lee
Nelson T K
NT
Yu
Hua
H
Pang
Yuanping
Y
Huang
Pingbo
P
Xia
Jun
J
Li
Zhi-Wang
ZW
Li
Chaoying
C
Han
Yifan
Y
D000495:Allosteric Site; D000818:Animals; D002478:Cells, Cultured; D019281:Dimerization; D006863:Hydrogen-Ion Concentration; D015640:Ion Channel Gating / Q000187:drug effects*; D016202:N-Methylaspartate / Q000494:pharmacology*; D011522:Protons; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013095:Spermidine / Q000494:pharmacology; D013619:Tacrine / Q000494:pharmacology*
D011522:Protons; D016194:Receptors, N-Methyl-D-Aspartate; D013619:Tacrine; D016202:N-Methylaspartate; D013095:Spermidine