Preferential block of T-type calcium channels by neuroleptics in neural crest-derived rat and human C cell lines.
We have used the whole-cell version of the patch-clamp technique to analyze the inhibition of Ca2+ currents by antipsychotic agents in neural crest-derived rat and human thyroid C cell lines. Diphenylbutylpiperidine (DPBP) antipsychotics, including penfluridol and fluspirilene, potently and preferentially block T-type Ca2+ current in the rat medullary thyroid carcinoma 6-23 (clone 6) cell line. When step depolarizations were applied at 0.1 Hz from a holding potential of -80 mV, with 10 mM Ca2+ as the charge carrier, the DPBP penfluridol inhibited T-type current with an IC50 of 224 nM. High voltage-activated L and N currents were less potently blocked. At a concentration of 500 nM, penfluridol inhibited 78.0 +/- 2.3% (n = 29) of inactivating T-type Ca2+ current, whereas the sustained high voltage-activated current was reduced by 25.6 +/- 3.5% (n = 28). Block of T-type current by penfluridol was enhanced by depolarizing test pulses applied at frequencies above 0.03 Hz. The use-dependent component of block was largely reversed by pulse-free periods at -80 mV. T-type Ca2+ channels in the human TT C cell line were blocked by penfluridol, and the potency was enhanced by reduction of extracellular Ca2+. Non-DPBP antipsychotics, including haloperidol, clozapine, and thioridazine, also blocked T-type channels, but these were 20-100 times less potent than the DPBPs. These results identify the DPBPs as a new class of organic Ca2+ channel antagonists, which are distinctive in their ability to preferentially block T-type channels. These agents will be useful in defining the function of T channels in various excitable cells. Their potent block of T-type Ca2+ channels, which would be enhanced in rapidly firing cells, suggests that this action may be relevant to the therapeutic or toxic effects of these drugs when used in clinical pharmacology.
Department of Pharmacology, Ohio State University College of Medicine, Columbus 43210-1239.
J J
JJ
Enyeart
B A
BA
Biagi
B
B
Mlinar
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000502:physiology; D004594:Electrophysiology; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D009432:Neural Crest / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D010395:Penfluridol / Q000494:pharmacology; D051381:Rats; D013964:Thyroid Neoplasms / Q000473:pathology / Q000503:physiopathology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D014150:Antipsychotic Agents; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D010395:Penfluridol