Inhibitory Effects of Clofilium on Membrane Currents Associated with Ca²⁺ Channels, NMDA Receptor Channels and Na⁺, K⁺-ATPase in Cortical Neurons

Abstract

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 µmol/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 µmol/l). At concentrations of >100 µmol/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 µmol/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.

Electrophysiological properties of human adipose tissue-derived stem cells

“…This is because the pharmacological action of clofilium tosylate is much more complex than previously anticipated. In addition to inhibiting K ϩ current, clofilium tosylate also inhibits Na ϩ current and Ca 2ϩ current (28,55). The inhibitory effect of clofilium tosylate on cell proliferation may due to its effect on these different ion channels.…”

Alternative Targets for Modulators of Mitochondrial Potassium Channels

“…Clofilium is another modulator of Slo2 channels. This inhibitor can modulate a broad spectrum of channels, including Slo3, Kv1.5 [ 264 ], and TASK-2 channels [ 265 ], as well as NMDA receptors [ 266 ]. NMDA inhibition was observed after the application of 0.1 μM of clofilium [ 266 ].…”

“…This inhibitor can modulate a broad spectrum of channels, including Slo3, Kv1.5 [ 264 ], and TASK-2 channels [ 265 ], as well as NMDA receptors [ 266 ]. NMDA inhibition was observed after the application of 0.1 μM of clofilium [ 266 ]. Clofilium can also induce apoptosis in human promyelocytic leukemia cells [ 267 ].…”

Arrhythmia and neuronal/endothelial myocyte uncoupling in hyperhomocysteinemia

“…Interestingly, increased levels of Hcy create myocardial conduction abnormalities and are associated with SCD Bollani et al, 1999;Burke et al, 2002). Hcy behaves as an agonist to NMDA-R1, and NMDA induces Ca2+ and K+ currents Yang et al, 2005). Treatment of spinal motor neurons with Hcy elevated [Ca2+]i which culminated in cell death (Adalbert et al, 2002).…”