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Fluspirilene block of N‐type calcium current in NGF‐differentiated PC 12 cells
Author(s) -
Grantham C.J.,
Main M.J.,
Cannell M.B.
Publication year - 1994
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1994.tb14762.x
Subject(s) - nifedipine , calcium channel , voltage dependent calcium channel , chemistry , calcium , t type calcium channel , patch clamp , n type calcium channel , biophysics , neurotransmitter , ic50 , electrophysiology , endocrinology , neuroscience , biochemistry , in vitro , receptor , biology , organic chemistry
1 High voltage‐activated calcium currents were recorded in nerve growth factor (NGF)‐differentiated PC12 cells with the whole‐cell patch clamp technique. After exposure to NGF for 3–10 days the PC12 cells developed neurone‐like processes and calcium currents which were pharmacologically separable into L‐ and N‐types (defined by sensitivity to nifedipine and ω‐conotoxin GVIA respectively). 2 After blocking the L‐type calcium channels with nifedipine (10 μ m ), ω‐conotoxin GVIA blocked approximately 85% of the remaining calcium current with an IC 50 of 3 n m and a Hill coefficient of 1. The block by conotoxin GVIA was irreversible on the time scale of these experiments. These results suggested that the majority of the nifedipine‐insensitive calcium current was N‐type. 3 Fluspirilene, a substituted diphenylbutylpiperidine with potent neuroleptic properties, reversibly inhibited the N‐type component in a dose‐dependent manner with an IC 50 of 30 n m . The Hill coefficient of the block was 0.25. The fraction of current blocked was the same at all test potentials examined (–30 to +40 mV). 4 These data indicate that the neuroleptic properties of fluspirilene may be due, at least in part, to an inhibition of neuronal N‐type calcium channels. This finding raises the possibility that modulation of N‐type calcium channel activity by drugs derived from substituted diphenylbutylpiperidines may provide a novel way of altering neurotransmitter release and hence brain function.