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The Journal of Neuroscience, January 15, 2002, 22(2):396-403
Differential Inhibition of T-Type Calcium Channels by
Neuroleptics
Celia M.
Santi1,
Francisco S.
Cayabyab2,
Kathy G.
Sutton1,
John E.
McRory1,
Janette
Mezeyova2,
Kevin S.
Hamming1,
David
Parker2,
Anthony
Stea3, and
Terrance P.
Snutch1
1 Biotechnology Laboratory, University of British
Columbia, Vancouver, British Columbia, Canada, V6T 1Z3,
2 NeuroMed Technologies, Vancouver, British Columbia,
Canada, V6T 1Z4, and 3 University-College of the Fraser
Valley, Abbotsford, British Columbia, Canada, V2S 7M8
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 ( 1G, 1H, and 1I
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 1G and 1I T-type
channels compared with 1H. 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.
Key words:
T-type; neuroleptics; cDNA; calcium channels; schizophrenia
Copyright © 2002 Society for Neuroscience 0270-6474/02/222396-08$05.00/0
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