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.
Enyeart
J J
JJ
Department of Pharmacology, Ohio State University College of Medicine, Columbus 43210-1239.
Biagi
B A
BA
Mlinar
B
B
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