 |
||||
|
||||
|
||||
|
||||
Previous Article | Next Article
The Journal of Neuroscience, December 15, 1999, 19(24):10611-10626
Probing of NMDA Channels with Fast Blockers
Alexander I. Sobolevsky, Sergey G. Koshelev, and Boris I. Khodorov Institute of General Pathology and Pathophysiology, 125315 Moscow, Russia
Using whole-cell patch-clamp techniques, we studied the interaction of open NMDA channels with tetraalkylammonium compounds: tetraethylammonium (TEA), tetrapropylammonium (TPA), tetrabutylammonium (TBA), and tetrapentylammonium (TPentA). Analysis of the blocking kinetics, concentration, and agonist dependencies using a set of kinetic models allowed us to create the criteria distinguishing the effects of these blockers on the channel closure, desensitization, and agonist dissociation. Thus, it was found that TPentA prohibited, TBA partly prevented, and TPA and TEA did not prevent either the channel closure or the agonist dissociation. TPentA and TBA prohibited, TPA slightly prevented, and TEA did not affect the channel desensitization. These data along with the voltage dependence of the stationary current inhibition led us to hypothesize that: (1) there are activation and desensitization gates in the NMDA channel; (2) these gates are distinct structures located in the external channel vestibule, the desensitization gate being located deeper than the activation gate. The size of the blocker plays a key role in its interaction with the NMDA channel gating machinery: small blockers (TEA and TPA) bind in the depth of the channel pore and permit the closure of both gates, whereas larger blockers (TBA) allow the closure of the activation gate but prohibit the closure of the desensitization gate; finally, the largest blockers (TPentA) prohibit the closure of both activation and desensitization gates. The mean diameter of the NMDA channel pore in the region of the activation gate localization was estimated to be ~11 Å.
Key words: NMDA; gating machinery; tetraalkylammonium compounds; blockade; desensitization; kinetics; patch-clamp; whole-cell; hippocampal neurons
Copyright © 1999 Society for Neuroscience 0270-6474/99/192410611-16$05.00/0
This article has been cited by other articles:
H.-R. Chang and C.-C. Kuo
The Activation Gate and Gating Mechanism of the NMDA Receptor
J. Neurosci., February 13, 2008; 28(7): 1546 - 1556.
[Abstract] [Full Text] [PDF]
S. M. Dravid, K. Erreger, H. Yuan, K. Nicholson, P. Le, P. Lyuboslavsky, A. Almonte, E. Murray, C. Mosley, J. Barber, et al.
Subunit-specific mechanisms and proton sensitivity of NMDA receptor channel block
J. Physiol., May 15, 2007; 581(1): 107 - 128.
[Abstract] [Full Text] [PDF]
C. G. Thomas, J. J. Krupp, E. E. Bagley, R. Bauzon, S. F. Heinemann, B. Vissel, and G. L. Westbrook
Probing N-Methyl-D-aspartate Receptor Desensitization with the Substituted-Cysteine Accessibility Method
Mol. Pharmacol., April 1, 2006; 69(4): 1296 - 1303.
[Abstract] [Full Text] [PDF]
N. Chen, B. Li, T. H. Murphy, and L. A. Raymond
Site within N-Methyl-D-aspartate Receptor Pore Modulates Channel Gating
Mol. Pharmacol., January 1, 2004; 65(1): 157 - 164.
[Abstract] [Full Text] [PDF]
M. F. Jackson, D. T. Joo, A. A. Al-Mahrouki, B. A. Orser, and J. F. Macdonald
Desensitization of {alpha}-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors Facilitates Use-Dependent Inhibition by Pentobarbital
Mol. Pharmacol., August 1, 2003; 64(2): 395 - 406.
[Abstract] [Full Text] [PDF]
A. I. Sobolevsky, L. Rooney, and L. P. Wollmuth
Staggering of Subunits in NMDAR Channels
Biophys. J., December 1, 2002; 83(6): 3304 - 3314.
[Abstract] [Full Text] [PDF]
X. Wang, A. Y. Xiao, T. Ichinose, and S. P. Yu
Effects of Tetraethylammonium Analogs on Apoptosis and Membrane Currents in Cultured Cortical Neurons
J. Pharmacol. Exp. Ther., November 1, 2000; 295(2): 524 - 530.
[Abstract] [Full Text]
|
|
|
|
 |
|