Overlapping selectivity of neurotoxin and dihydropyridine calcium channel blockers in cerebellar granule neurones

Calcium (Ca2+) currents have been studied extensively in cerebellar granule neurones, but much of the whole-cell pharmacology is inconsistent. Ca2+ ch annel currents were recorded from granule neurones to investigate whether t he commonly used Ca2+ channel blockers show overlapping selectivity. Using combinations of toxin channel blockers, 45% of the total current was shown to be carried by Ca2+ channels susceptible to block by the combined, or cumulative application of, omega-agatoxin IVA, omega-conotoxin GVIA and omega-conotoxin MVIIC, thus representing P/Q- and N-type channel currents. However, sequential application of these toxins showed that substantial ove rlap occurred in the proportions of current sensitive to individual toxins. Application of the 1,4-dihydropyridine nicardipine at 1 mu M, a concentrat ion reported to be selective for L-type channels, blocked 16% of the total current, without reducing the current sensitive to the toxins used. However , greater concentrations of nicardipine (> 10 mu M) blocked a proportion of the total current that could not be accounted for by L-type channels alone . These results demonstrate that a pharmacological approach based on the L, N , P/Q, and R classification does not adequately describe the Ca2+ channel s ubtypes found in cerebellar granule neurones due to substantial cross-selec tivity to the drugs and toxins used. (C) 2000 Elsevier Science Ltd. All rig hts reserved.