Fluspirilene block of N-type calcium current in NGF-differentiated PC12 cells.
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 omega-conotoxin GVIA respectively). 2. After blocking the L-type calcium channels with nifedipine (10 microM), omega-conotoxin GVIA blocked approximately 85% of the remaining calcium current with an IC50 of 3 nM 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 IC50 of 30 nM. 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.
Grantham
C J
CJ
Department of Pharmacology, St. George's Hospital Medical School, London.
Main
M J
MJ
Cannell
M B
MB
D000818:Animals; D002104:Cadmium / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D003470:Culture Media; D004594:Electrophysiology; D005484:Fluspirilene / Q000494:pharmacology*; D007700:Kinetics; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009543:Nifedipine / Q000494:pharmacology; D016716:PC12 Cells; D010455:Peptides / Q000494:pharmacology; D020866:omega-Conotoxin GVIA
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D003470:Culture Media; D009414:Nerve Growth Factors; D010455:Peptides; D002104:Cadmium; D020866:omega-Conotoxin GVIA; D005484:Fluspirilene; D009543:Nifedipine