title: Differential inhibition of T-type calcium channels by neuroleptics.
abstract: T-type calcium channels play critical roles in cellular excitability and have been implicated in the pathogenesis of a variety of neurological disorders including epilepsy. Although there have been reports that certain neuroleptics that primarily target D2 dopamine receptors and are used to treat psychoses may also interact with T-type Ca channels, there has been no systematic examination of this phenomenon. In the present paper we provide a detailed analysis of the effects of several widely used neuroleptic agents on a family of exogenously expressed neuronal T-type Ca channels (alpha1G, alpha1H, and alpha1I subtypes). Among the neuroleptics tested, the diphenylbutylpiperidines pimozide and penfluridol were the most potent T-type channel blockers with Kd values (approximately 30-50 nm and approximately 70-100 nm, respectively), in the range of their antagonism of the D2 dopamine receptor. In contrast, the butyrophenone haloperidol was approximately 12- to 20-fold less potent at blocking the various T-type Ca channels. The diphenyldiperazine flunarizine was also less potent compared with the diphenylbutylpiperadines and preferentially blocked alpha1G and alpha1I T-type channels compared with alpha1H. The various neuroleptics did not significantly affect T-type channel activation or kinetic properties, although they shifted steady-state inactivation profiles to more negative values, indicating that these agents preferentially bind to channel inactivated states. Overall, our findings indicate that T-type Ca channels are potently blocked by a subset of neuroleptic agents and suggest that the action of these drugs on T-type Ca channels may significantly contribute to their therapeutic efficacy.
authors.affiliation: Biotechnology Laboratory, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Celia M
authors.initials: CM
authors.lastname: Santi
authors.forename: Francisco S
authors.initials: FS
authors.lastname: Cayabyab
authors.forename: Kathy G
authors.initials: KG
authors.lastname: Sutton
authors.forename: John E
authors.initials: JE
authors.lastname: McRory
authors.forename: Janette
authors.initials: J
authors.lastname: Mezeyova
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Hamming
authors.forename: David
authors.initials: D
authors.lastname: Parker
authors.forename: Anthony
authors.initials: A
authors.lastname: Stea
authors.forename: Terrance P
authors.initials: TP
authors.lastname: Snutch
mesh_terms: D014150:Antipsychotic Agents / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020747:Calcium Channels, T-Type / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005444:Flunarizine / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010395:Penfluridol / Q000494:pharmacology; D010868:Pimozide / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D014162:Transfection
chemical_list: D014150:Antipsychotic Agents; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D010880:Piperidines; D010868:Pimozide; D010395:Penfluridol; D006220:Haloperidol; D005444:Flunarizine