Evidence for Inhibitory Effects of Flupirtine, a Centrally Acting Analgesic, on Delayed Rectifier K⁺Currents in Motor Neuron-Like Cells

Abstract

Flupirtine (Flu), a triaminopyridine derivative, is a centrally acting, non-opiate analgesic agent. In this study, effects of Flu on K+ currents were explored in two types of motor neuron-like cells. Cell exposure to Flu decreased the amplitude of delayed rectifier K+ current (I K(DR)) with a concomitant raise in current inactivation in NSC-34 neuronal cells. The dissociation constant for Flu-mediated increase of I K(DR) inactivation rate was about 9.8 μM. Neither linopirdine (10 μM), NMDA (30 μM), nor gabazine (10 μM) reversed Flu-induced changes in I K(DR) inactivation. Addition of Flu shifted the inactivation curve of I K(DR) to a hyperpolarized potential. Cumulative inactivation for I K(DR) was elevated in the presence of this compound. Flu increased the amplitude of M-type K+ current (I K(M)) and produced a leftward shift in the activation curve of I K(M). In another neuronal cells (NG108-15), Flu reduced I K(DR) amplitude and enhanced the inactivation rate of I K(DR). The results suggest that Flu acts as an open-channel blocker of delayed-rectifier K+ channels in motor neurons. Flu-induced block of I K(DR) is unlinked to binding to NMDA or GABA receptors and the effects of this agent on K+ channels are not limited to its action on M-type K+ channels.

Pioglitazone, a PPAR-γ Activator, Stimulates BKCa but Suppresses IKM in Hippocampal Neurons

“…In continued presence linopirdine, further application of 10 μM flupirtine significantly reversed linopirdine-induced inhibition of I K ( M ) in mHippoE-14 neurons ( Figure 6 ). Moreover, in continued presence of 10 μM PIO, subsequent addition of 10 μM flupirtine, an activator of I K ( M ) (Wu et al, 2012), was found to reverse its inhibition of I K ( M ) ( Figure 7 ). Therefore, it is possible that the presence of PIO suppressed the amplitude of I K ( M ) effectively in mHippoE-14 hippocampal neurons.…”

Important modifications by sugammadex, a modified γ-cyclodextrin, of ion currents in differentiated NSC-34 neuronal cells

“…It has been demonstrated to be a suitable model for investigations on the mechanisms of neuronal development and differentiation in vitro and for studying electrophysiological properties of motor neurons in spite of being not considered as an adult motor neuron [18–20]. The biophysical properties of delayed-rectifier K + current [ I K(DR) ] in NSC-34 cells were previously found to resemble the K V 3.1-encoded current because of positive mRNA detection of K V 3.1 ( KCNC1 ) [21, 22]. As NSC-34 cells were differentiated, the density of I K(DR) was significantly enhanced.…”

Blockade of voltage-gated K+ currents in rat mesenteric arterial smooth muscle cells by MK801

“…5). Although alterations in the steady-state activation and inactivation curves are not strictly required in state-dependent drug-channel interaction, most state-dependent channel blockers alter the steady-state channel kinetics (such as a left-shift of inactivation) (49,50). Third, when spontaneous channel activation and inactivation were prevented by holding E m at a hyperpolarized potential (À110 mV), the first depolarizing pulse after the~2-min treatment with MK801 produced an identical degree and pattern of Kv-channel inhibition as in the steady-state experiments (Fig.…”

“…In the cardiovascular system, MK801 induces hypertension and tachycardia (12,13), much as ketamine does. MK801 has been reported to produce psychomotor and anesthetic effects that are almost indistinguishable from those Abbreviations: 5-HT 2A R, 5-HT 2A receptor; BAPTA, 1,2-bis(aminophenoxy) ethane-N,N,N 0 ,N 0 -tetraacetic acid; BK Ca , big conductance Ca 2þ -activated K þ ; CNS, central nervous system; E m , membrane potential; G m , membrane conductance; GPCR, G-protein coupled receptor; IeV, currentevoltage; IC 50 , half inhibition concentration; Kv channel, voltage-gated K þ channel; n, Hill coefficient; NMDAr, NMethyl-D-aspartate receptor; NT, normal Tyrode; PCP, phencyclidine; RMASMCs, rat mesenteric arterial smooth muscle cells; SD, SpragueeDawley. observed after treatment with traditional dissociative NMDArantagonist anesthetics such as PCP and ketamine.…”