ON THE INHIBITION OF VOLTAGE-ACTIVATED CALCIUM CURRENTS IN RAT CORTICAL-NEURONS BY THE NEUROPROTECTIVE AGENT 619C89

1 The lamotrigine analogue 619C89, utilised to reduce postischaemic an d posttraumatic neuronal injury, has been shown to inhibit sodium chan nels and cloned N-type calcium channels. To verify whether this neurop rotective agent also blocked native calcium channels, we have tested i ts action in cortical pyramidal neurones, acutely isolated from the ad ult rat brain. 2 619C83 inhibited more than 90% of the high voltage-ac tivated calcium currents recorded in the whole-cell configuration. The response was relatively slow in onset (30-60 s), recovered incomplete ly (96%), but showed no consistent desensitization. 3 This inhibitory effect was not selective for any calcium channel subtype, being largel y unaffected by omega-conotoxin-GVIA, omega-agatoxin-IVA, omega-conoto xin-MVIIC and dihydropyridine antagonists. 4 Saturating responses to 6 19C89 were detected for concentrations greater than or equal to 50 mu M. Dose-response curves revealed that 619C89 have an approximately 8 m u M binding site. 5 The effect of 619C89 was dependent an the divalent concentrations in that its potency was reduced on increase of the cha rge carrier up to 20 mM barium. Since the lamotrigine analogue shifted to the right the dose-dependence of the cadmium block, the 619C89-med iated inhibition of calcium currents seemed to rely on a direct intera ction with the channel pore. Functional implications are discussed.