Characterization of the K+ channel opening effect of the anticonvulsant retigabine in PC12 cells

Epilepsy Res. 1999 Jun;35(2):99-107. doi: 10.1016/s0920-1211(98)00131-4.

Abstract

Retigabine (D-23129) is a new anticonvulsant compound which acts as a K+ channel opener in neuronal cells. The aim of the present study was to further characterize the retigabine induced K+ current. In nerve growth factor treated PC12 cells and in rat cortical neurones the application of retigabine activated a K+ current. In contrast, however, no K+ current activation was observed in untreated PC12 and in glial cells which were cultivated together with the neuronal cells. To characterise the retigabine activated K+ current, K+ channel blockers were used. The retigabine induced current was not affected by 1 and 10 mM 4-aminopyridine (4AP). Ba2+ 1 mM resulted in a reduction of 88.6+/-3.0% (n = 5); 10 mM abolished the current. Tetraetylamonium (TEA), 1 and 10 mM, reduced the current by 23.6+/-3.1 and 61.6+/-3.7%, respectively. To investigate the current/voltage (I/V) relation of the current initiated by retigabine (10 microM), cells were clamped to a holding potential of -80 mV and a ramp stimulation protocol (-120 to +60 mV in 5 s) was applied prior to and during application of retigabine. Subtraction of the two traces yielded the current induced by retigabine. A nearly linear relationship was determined between - 120 and -40 mV. At potentials positive to - 40 mV, the response was variable. This was due to the additionally observed weak blocking effect of retigabine on delayed rectifier (Kdr) currents. If the ramp was applied in the presence of 10 mM 4AP to block Kdr, a nearly linear I/V-relationship was present from -120 to +60 mV. The comparison of the I/V relation and pharmacology with published K+ channel subtypes gives evidence that an unknown neuronal K+ channel subtype may be involved.

MeSH terms

  • Animals
  • Anticonvulsants / pharmacology*
  • Carbamates / pharmacology*
  • Cells, Cultured
  • Electrophysiology
  • Epilepsy / drug therapy
  • Epilepsy / metabolism
  • Nerve Growth Factor / pharmacology
  • PC12 Cells
  • Phenylenediamines / pharmacology*
  • Potassium Channels / drug effects*
  • Rats

Substances

  • Anticonvulsants
  • Carbamates
  • Phenylenediamines
  • Potassium Channels
  • ezogabine
  • Nerve Growth Factor