The voltage- and time-dependent blocking effect of trifluoperazine on T lymphocyte Kv1.3 channels

• Published in: Biochemical pharmacology Vol. 65; no. 4; pp. 551 - 561
• Main Authors: Teisseyre, Andrzej, Michalak, Krystyna
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 15-02-2003; Elsevier Science
• Subjects: Biological and medical sciences; Electrophysiology; Humans; In Vitro Techniques; Kv1.3 Potassium Channel; Medical sciences; Membrane Potentials - drug effects; Neuropharmacology; Patch-clamp; Pharmacology. Drug treatments; Phenothiazines; Potassium channel; Potassium Channel Blockers - pharmacology; Potassium Channels - metabolism; Potassium Channels - physiology; Potassium Channels, Voltage-Gated; Psycholeptics: tranquillizer, neuroleptic; Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; T lymphocyte; T-Lymphocytes - drug effects; T-Lymphocytes - metabolism; T-Lymphocytes - physiology; Time Factors; Trifluoperazine; Trifluoperazine - pharmacology; TL, human T lymphocyte; V i, inactivation midpoint; Trifluoperazine; Phenothiazines; τ i, inactivation time constant; V rev, reversal potential of the current; I rel, relative peak current; I contr60, current amplitude recorded on the same cell under control conditions at +60 mV; g K −120, chord conductance recorded on the same cell from the holding potential of −120 mV; Patch-clamp; g K, chord conductance; TMX, tamoxifen; τ n, activation time constant; TFP, trifluoperazine; g K norm, normalised relative chord conductance; V n, activation midoint; I, current amplitude; 4-AP, 4-aminopyridine; k i, steepness of the voltage dependence (inactivation); T lymphocyte; g K 60, chord conductance recorded on the same cell at +60 mV; V, membrane potential; k n, steepness of the voltage dependence (activation); Potassium channel; Potassium Cations; Neuroleptic; Psychotropic; Electrophysiology; Patch clamp method; Activation; Ionic channel; Phenothiazine derivatives; Ionic current; Inactivation; Concentration effect; T-Lymphocyte; Membrane potential
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/S0006-2952(02)01561-7

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
μM 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
μM 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 +60
mV and least potent at −20
mV. 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.