Inhibitory effects of clofilium on membrane currents associated with Ca channels, NMDA receptor channels and Na+, K+-ATPase in cortical neurons.
The class III antiarrhythmic agent 4-chloro-N,N-diethyl-N-heptyl-benzene butanaminium (clofilium) is known as a K+ channel open-channel blocker and has either anti- or proapoptotic property due to undefined mechanisms. Based on the evidence that neuronal viability is largely, sometimes critically, affected by voltage- and ligand-gated Ca2+ channels and the Na+, K+-ATPase, we tested the hypothesis that clofilium might additionally act on Ca2+ permeable ion channels and the Na+, K+-ATPase. Membrane currents associated with activities of voltage-gated Ca2+ channels, N-methyl-D-aspartate (NMDA) receptor channels and Na+, K+-ATPase were recorded using whole-cell recordings in cultured murine cortical neurons. Clofilium (0.1-100 micromol/l) inhibited high voltage-activated Ca2+ currents in concentration- and use-dependent manners. Clofilium acted as a potent antagonist of NMDA receptor channels, preferably blocked the NMDA steady-state current at a low concentration (0.1 micromol/l). At concentrations of >100 micromol/l, clofilium blocked both peak and steady-state NMDA currents in a voltage-independent manner. Clofilium also inhibited the Na+, K+-ATPase current with an IC50 of 7.5 micromol/l. Our data suggest that the pharmacological action of clofilium is far more complex than recognized before; the multiple actions of clofilium on membrane conductance may explain its diverse effects on cellular events and cell viability.
Yang
Aizhen
A
Department of Pharmaceutical Sciences, College of Pharmacy, Medical University of South Carolina, Charleston, SC 29425, USA.
Wang
Xue Qing
XQ
Sun
Chuan-Shu
CS
Wei
Ling
L
Yu
Shan Ping
SP
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000502:physiology; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors* / Q000502:physiology
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004791:Enzyme Inhibitors; D000644:Quaternary Ammonium Compounds; D016194:Receptors, N-Methyl-D-Aspartate; C022799:clofilium; D000254:Sodium-Potassium-Exchanging ATPase