PT  - JOURNAL ARTICLE
AU  - Celia M. Santi
AU  - Francisco S. Cayabyab
AU  - Kathy G. Sutton
AU  - John E. McRory
AU  - Janette Mezeyova
AU  - Kevin S. Hamming
AU  - David Parker
AU  - Anthony Stea
AU  - Terrance P. Snutch
TI  - Differential Inhibition of T-Type Calcium Channels by Neuroleptics
AID  - 10.1523/JNEUROSCI.22-02-00396.2002
DP  - 2002 Jan 15
TA  - The Journal of Neuroscience
PG  - 396--403
VI  - 22
IP  - 2
4099  - http://www.jneurosci.org/content/22/2/396.short
4100  - http://www.jneurosci.org/content/22/2/396.full
SO  - J. Neurosci.2002 Jan 15; 22
AB  - 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 D2dopamine 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 α1Isubtypes). 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.