Inhibitory effects of pimozide on cloned and native voltage-gated potassium channels.
The primary goal of this study was to use the cloned neuronal Kv channels to test if pimozide (PMZD), an antipsychotic drug, modulates the activity of Kv channels. In CHO cells, PMZD blocked Kv2.1, a major neuronal delayed rectifier, in a manner that depends upon time and concentration. The estimated IC50 was 4.2 microM at +50 mV. Tail current analysis shows that PMZD reduced the amplitude of the currents, with no effect on the steady-state activation curve (V(1/2) from 14.1 to 11.1 mV) or the slope (16.7 vs. 14.0 mV). From -120 to -20 mV, PMZD did not impact the deactivation kinetics of Kv2.1. PMZD also blocked Kv1.1, another neuronal delayed rectifier, with 16.1 microM of IC50. When Kv1.1 was co-expressed with Kvbeta1, approximately 50% of the Kv1.1 were converted into an inactivating A-type current and the Kv1.1/Kvbeta1 A-type currents were insensitive to PMZD. PMZD (10 microM) had minimal effect on Kv1.4, and had no effect on the M-current candidates, KCNQ2 and KCNQ3 when co-expressed in Xenopus oocytes. In hippocampal neurons, PMZD inhibited the delayed rectifiers by approximately 60%, and A-type currents were insensitive to PMZD. The results suggest that PMZD inhibits certain neuronal Kv channels in heterologous expression systems and in hippocampal neurons. PMZD was less effective on A-type currents, presumably because its ability to block requires a prolonged opening of the K channels. It is thus conceivable that the time-dependent and/or subunit-specific inhibition of Kv channels may increase the release of neurotransmitters such as serotonin and glutamate.
Zhang
Zhi-Hao
ZH
Department of Neuroscience, Wyeth Research, Princeton, NJ, USA.
Lee
Yan T
YT
Rhodes
Kenneth
K
Wang
Kewei
K
Argentieri
Thomas M
TM
Wang
Qiang
Q
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D016466:CHO Cells; D003001:Cloning, Molecular; D006224:Cricetinae; D051668:Delayed Rectifier Potassium Channels; D004305:Dose-Response Relationship, Drug; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051658:KCNQ2 Potassium Channel; D051659:KCNQ3 Potassium Channel; D051662:Kv1.1 Potassium Channel; D001523:Mental Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009865:Oocytes; D009924:Organ Culture Techniques; D010868:Pimozide / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects / Q000235:genetics; D051669:Shab Potassium Channels; D014982:Xenopus laevis
D014150:Antipsychotic Agents; D051668:Delayed Rectifier Potassium Channels; D051658:KCNQ2 Potassium Channel; D051659:KCNQ3 Potassium Channel; C496991:Kcnb1 protein, rat; C496915:Kcnq2 protein, rat; C496918:Kcnq3 protein, rat; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D051669:Shab Potassium Channels; D051662:Kv1.1 Potassium Channel; D010868:Pimozide