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528199 
Journal Article 
Blockade of ion channels of NMDA and AMPA subtypes of glutamate receptors by dicationic derivative of phenylcyclohexyl (IEM-1925) 
Tikhonova, TB; Tikhonov, DB; Magazanik, LG 
2005 
22 
4 
290-299 
Russian 
The action of dicationic derivative of phenylcyclohexyl IEM-1925 on NMDA and Ca2+-permeable AMPA-receptors was studied using whole-cell patch-clamp technique. This compound is a potent open-channel blocker of both types of receptors: apparent half-blocicing concentration (lC(50)) at -80 mV was 1.2 +/- 0.8 mu M (n = 7) for NMDA receptor channels and 1.4 +/- 0.6 pM (n = 5) for AMPA receptor channels. The kinetics of IEM-1925 action was also similar for NMDA and AMPA channels. It makes IEM-1925 a good toot for comparison of the blockade mechanisms of these channels. Blockade of NMDA receptor channels was more voltage-dependent than blockade of AMPA receptor channels: the apparent values of delta were 0.37 +/- 0.12 (n = 8) for AMPA and 0.9 +/- 0.1 (n = 7) for NMDA channels. Being the open channel blocker, IEM-1925 can be "trapped" in the closed channels of both AMPA and NMDA receptors. To calculate the degree of "trapping" the double-pulse protocol was used. The effect of "trapping" in NMDA channels was voltage-dependent: the degree of "trapping" at -80 and -40 mV was 55 +/- 6% (n = 6) and 26 +/- 9% (n = 7), respectively. In contrast, there was no voltage-dependence of "trapping" in the channels of AMPA receptors. The "trapping" in AMPA channels measured after 25 s of washout without agonist was 73 +/- 9% (n = 8). This value decreased to 33 +/- 2% (n = 4) for 150 s washout. Time-dependence of "trapping" in the channels of AMPA receptors possibly indicates that IEM-1925 can leave the closed AMPA channels. The kinetics of this process did not differ at holding potentials -40 and -80 mV. Time dependence of "trapping" in NMDA channels was not revealed. The ability of IEM-1925 to leave the closed AMPA receptor channel prompted us to check if the blocker can enter the closed channel, producing a blockade in the absence of agonist. However, 5-minute application of 500 mu M (about 500 x IC50) IEM-1925 did not lead to blockade of NMDA and AMPA channels, so the enter of IEM-1925 into the closed channels did not happen. The data obtained suggest different molecular determinants of interaction of IEM-1925 with NMDA and AMPA receptor channels. 
methyl-d-aspartate; structural determinants; hippocampal-neurons; rat; hippocampal; binding-sites; patch-clamp; amantadine; memantine; kinetics; brain