Overlapping selectivity of neurotoxin and dihydropyridine calcium channel blockers in cerebellar granule neurones.
Calcium (Ca(2+)) currents have been studied extensively in cerebellar granule neurones, but much of the whole-cell pharmacology is inconsistent. Ca(2+) channel currents were recorded from granule neurones to investigate whether the commonly used Ca(2+) channel blockers show overlapping selectivity. Using combinations of toxin channel blockers, 45% of the total current was shown to be carried by Ca(2+) 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 microM, 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 microM) 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 Ca(2+) channel subtypes found in cerebellar granule neurones due to substantial cross-selectivity to the drugs and toxins used.
Burley
J R
JR
Department of Pharmacology, Medawar Building, University College London, Gower Street, WC1E 6BT, London, UK. uckljrb@ucl.ac.uk
Dolphin
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D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D004095:Dihydropyridines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D009498:Neurotoxins / Q000494:pharmacology*; D009529:Nicardipine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020867:omega-Agatoxin IVA / Q000494:pharmacology; D020866:omega-Conotoxin GVIA / Q000494:pharmacology; D020960:omega-Conotoxins / Q000494:pharmacology
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D004095:Dihydropyridines; D009498:Neurotoxins; D020867:omega-Agatoxin IVA; D020960:omega-Conotoxins; C075851:omega-conotoxin-MVIIC; D020866:omega-Conotoxin GVIA; D009529:Nicardipine