Mechanisms of the blockade of glutamate channel receptors: significance for structural and physiological investigations.
The mechanism of the blocking action of phenylcyclohexyl derivative IEM-1925 on ionotropic NMDA and AMPA glutamate receptors was studied. Experiments on isolated rat brain neurons (hippocampal pyramidal cells and striatal cholinergic interneurons) were performed using local voltage clamping in the "whole cell" configuration. In equilibrium conditions at a membrane potential of -80 mV, there was no selectivity in the action of IEM-1925 on the open channels of either type of glutamate receptor. However, data were obtained showing significant differences in the mechanisms of the blocking actions. Although IEM-1925 was unable to penetrate into closed channels of either receptor type, molecules were able to leave closed AMPA receptor channels but not closed NMDA receptor channels. In hyperpolarization, the departure of the blocker from open NMDA receptor channels was slowed, while departure from open and closed AMPA receptor channels was accelerated. The blocker thus appeared able to penetrate AMPA receptor channels to enter cells, the gating mechanism of these channels being located above the blocker binding site. The actions of IEM-1925 on NMDA and AMPA receptors were compared with its ability to suppress tremor in mice induced with s.c. doses of arecoline. The results indicated that both types of receptors have a role in producing tremor. The differences in the mechanisms of action on AMPA and NMDA receptors may explain the ambiguous nature of the effects of the glutamate channel blocker in experimental therapy.
Magazanik
L G
LG
I. M. Sechenov Institute of Evolutionary Physiology and Biochemistry, St. Petersburg, Russia.
Tikhonov
D B
DB
Tikhonova
T B
TB
Lukomskaya
N Ya
NY
D000818:Animals; D000831:Animals, Newborn; D001115:Arecoline; D003959:Diamines / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004347:Drug Interactions; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D006624:Hippocampus / Q000166:cytology; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology*; D007608:Kainic Acid / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D051379:Mice; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques / Q000379:methods; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D017470:Receptors, Glutamate / Q000737:chemistry / Q000145:classification / Q000502:physiology*; D014202:Tremor / Q000139:chemically induced / Q000188:drug therapy
D003959:Diamines; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; C406748:IEM 1925; D000644:Quaternary Ammonium Compounds; D017470:Receptors, Glutamate; D001115:Arecoline; D016202:N-Methylaspartate; D007608:Kainic Acid