Differential inhibition of T-type calcium channels by neuroleptics

Celia M. Santi, Francisco S. Cayabyab, Kathy G. Sutton, John E. McRory, Janette Mezeyova, Kevin S. Hamming, David Parker, Anthony Stea, Terrance P. Snutch

Research output: Contribution to journalArticlepeer-review

146 Scopus citations

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 (α1G, α1H, and α1I subtypes). Among the neuroleptics tested, the diphenylbutylpiperidines pimozide and penfluridol were the most potent T-type channel blockers with Kd values (∼30-50 nM and ∼70-100 nM, respectively), in the range of their antagonism of the D2 dopamine receptor. In contrast, the butyrophenone haloperidol was ∼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 α1G and α1I, T-type channels compared with α1H. 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.

Original languageEnglish
Pages (from-to)396-403
Number of pages8
JournalJournal of Neuroscience
Volume22
Issue number2
DOIs
StatePublished - Jan 15 2002

Keywords

  • Calcium channels
  • Neuroleptics
  • Schizophrenia
  • T-type
  • cDNA

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