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+ channel currents were recorded from granule neurones to investigate whether the 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 overlap occurred in the proportions of current sensitive to individual toxins. Application of the 1,4-dihydropyridine nicardipine at 1 mu M, a concentration 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 subtypes found in cerebellar granule neurones due to substantial cross-selectivity to the drugs and toxins used. (C) 2000 Elsevier Science Ltd. All rights reserved.