Effects of midazolam on ion currents and membrane potential in differentiated motor neuron-like NSC-34 and NG108-15 cells

Abstract

Midazolam (MDL) was known to act through stimulation of benzodiazepine receptors (GABA). Whether midazolam affects ion currents and membrane potential in neurons remains largely unclear. Electrophysiological studies of midazolam actions were performed in differentiated motor neuron-like (NSC-34 and NG108-15) cells. Midazolam suppressed the amplitude of delayed rectifier K(+) current (IK(DR)) in a time- and concentration-dependent manner with an IC50 value of 10.4 µM. Addition of midazolam was noted to enhance the rate of IK(DR) inactivation. On the basis of minimal binding scheme, midazolam-induced block of IK(DR) was quantitatively provided with a dissociation constant of 9.8 µM. Recovery of IK(DR) from inactivation in the presence of midazolam was fitted by a single exponential. midazolam had no effect on M-type or erg-mediated K(+) current in these cells. Midazaolam (30 µM) suppressed the peak amplitude of voltage-gated Na(+) current (INa) with no change in the current-voltage relationships of this current. Inactivation kinetics of INa remained unaltered in the presence of this agent. In current-clamp configuration, midazolam (30 µM) prolonged the duration of action potentials (APs) and reduce AP amplitude. Similarly, in differentiated NG108-15 cells, the exposure to midazolam also suppressed IK(DR) with a concomitant increase in current inactivation. Midazolam can act as an open-channel blocker of delayed-rectifier K(+) channels in these cells. The synergistic blocking effects on IK(DR) and INa may contribute to the underlying mechanisms through which midazolam affects neuronal function in vivo.

Keywords: Apamin (PubChem CID: 16218850); Delayed rectifier K(+) current; Flupirtine (PubChem CID : 53276); Membrane potential; Methadone (PubChem CID: 4095); Midazolam; Midazolam (PubChem CID: 4192); Motor neuron-like cells; Tetrodotoxin (PubChem CID: 11174599); Voltage-gated Na(+) current.