The voltage- and time-dependent blocking effect of trifluoperazine on T lymphocyte Kv1.3 channels.
Phenothiazines are well-known calmodulin inhibitors that interact with many receptors and channels including a variety of potassium channels. In this study, we report a blocking effect of trifluoperazine (TFP) on voltage-gated Kv1.3 channels expressed in human T lymphocytes. Application of TFP in the concentration range from 1 to 20 microM reduced the current amplitude to about a half of the control value. The currents were blocked to less than 0.05 of the control value at 50 microM TFP concentration. The blocking effect was accompanied by a substantial increase in the current inactivation rate, whereas the activation rate and the steady-state activation and inactivation were not changed significantly. The blocking effect of TFP was voltage dependent being most potent at +60mV and least potent at -20mV. The blocking effect of TFP on the currents and the recovery from block was time dependent. Other calmodulin antagonists: tamoxifen (TMX) and thioridazine also inhibited the channels at micromolar concentrations. The effects exerted by TMX and thioridazine resembled the inhibitory effect of TFP. The blocking effect of thioridazine was time dependent and appeared to be more potent that the inhibition by TFP and TMX. TFP, TMX and thioridazine inhibited the activity of Kv1.3 channels only when applied extracellularly. The inhibitory effect of all the compounds was reversible. The possible physiological significance of the current inhibition is discussed.
Teisseyre
Andrzej
A
Department of Biophysics, Wrocław Medical University, ul. Chałubińskiego 10, 50-368 Wrocław, Poland. ateiss@biofiz.am.wroc.pl
Michalak
Krystyna
K
D004594:Electrophysiology; D006801:Humans; D066298:In Vitro Techniques; D051664:Kv1.3 Potassium Channel; D008564:Membrane Potentials / Q000187:drug effects; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D015221:Potassium Channels / Q000378:metabolism* / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D013997:Time Factors; D014268:Trifluoperazine / Q000494:pharmacology*
C496973:KCNA3 protein, human; D051664:Kv1.3 Potassium Channel; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D014268:Trifluoperazine