Inhibition of P-type and N-type calcium channels by dopamine receptor antagonists.
P-type Ca2+ channels in cerebellar Purkinje neurons and N-type Ca2+ channels in sympathetic neurons were found to be inhibited by D2 dopamine receptor antagonists with diverse structures, including phenothiazines (chlorpromazine and thioridazine), diphenylbutylpiperidines (fluspirilene and pimozide), butyrophenones (haloperidol and spiperone), and a piperazine (fluphenazine). Dopamine and quinpirole had no effect on P-type Ca2+ channels. In all cases, inhibition was characterized by slow onset and offset. The effects of P-type and N-type channels were very similar. Fluspirilene was the most potent of the drugs, with EC50 values of 6 microM for P-type current and 2 microM for N-type current. Block of P-type channels by fluspirilene was voltage dependent, being enhanced by depolarized holding potentials, and use dependent, being enhanced by higher stimulation frequencies. The effect of fluspirilene on the P-type Ca2+ channel current was not prevented by simultaneous exposure to the peptide toxin omega-agatoxin IVA, indicating that fluspirilene binds to a distinct site on the channel. The results suggest that N-type and P-type Ca2+ channels possess similar binding sites for dopamine receptor antagonists and that block of N-type and P-type channels is relatively weak, compared with that of some T-type and L-type Ca2+ channels.
Sah
D W
DW
Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115.
Bean
B P
BP
D000818:Animals; D002121:Calcium Channel Blockers; D018492:Dopamine Antagonists; D005484:Fluspirilene / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011689:Purkinje Cells / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D013881:Thioridazine / Q000494:pharmacology
D002121:Calcium Channel Blockers; D018492:Dopamine Antagonists; D005484:Fluspirilene; D013881:Thioridazine