Voltage-dependent biphasic effects of chloroquine on delayed rectifier K(+)-channel currents in murine thymocytes
I Kazama1, Y Maruyama, Y Murata
1Department of Physiology I, Tohoku University Graduate School of Medicine, Seiryo-cho, Aoba-ku, Sendai, Miyagi, Japan. kazaitsu@med.tohoku.ac.jp
Insights
Chloroquine has surprising biphasic effects on lymphocyte Kv1.3 potassium channels. This anti-malarial drug enhances peak currents while suppressing end currents, altering channel activation and inactivation.
Area of Science:
- Immunology
- Pharmacology
- Channel Physiology
Background:
- Lymphocytes express Kv1.3 potassium channels crucial for activation and proliferation.
- Chloroquine, an anti-malarial, has known immunosuppressive effects.
- Kv1.3 channels are potential targets for modulating lymphocyte function.
Purpose of the Study:
- To investigate the effects of chloroquine on Kv1.3 channel currents in murine thymocytes.
- To elucidate the voltage-dependent mechanisms underlying chloroquine's impact on these channels.
- To understand how chloroquine influences lymphocyte activation and proliferation via Kv1.3 channels.
Main Methods:
- Utilized the standard patch-clamp whole-cell recording technique.
- Examined Kv1.3 channel currents in murine thymocytes.
- Analyzed the voltage-dependent effects of chloroquine on channel activation and inactivation.
Main Results:
- Chloroquine suppressed Kv1.3 pulse-end currents at higher voltages.
- Surprisingly, chloroquine enhanced Kv1.3 peak currents at both high and low voltages.
- Chloroquine shifted activation and inactivation curves towards hyperpolarizing potentials, more pronounced at lower voltages.
Conclusions:
- Chloroquine exhibits voltage-dependent biphasic effects on thymocyte Kv1.3 channels.
- The drug facilitates both activation and inactivation of Kv1.3 channel currents.
- These findings suggest a complex interaction between chloroquine and lymphocyte potassium channels, potentially underlying its immunosuppressive actions.
Abstract:
Lymphocytes are of rich in delayed rectifier K(+)-channels (Kv1.3) in their plasma membranes, and the channels play crucial roles in the lymphocyte activation and proliferation. Since chloroquine, a widely used anti-malarial drug, exerts immunosuppressive effects, it will affect the channel currents in lymphocytes. In the present study, employing the standard patch-clamp whole-cell recording technique, we examined the effects of chloroquine on the channels expressed in murine thymocytes. Published papers report that chloroquine will inhibit voltage-dependent K(+)-channel currents by plugging into the open-pore. We observed, indeed, that chloroquine suppressed the pulse-end currents of Kv1.3-channels at higher voltage steps. Surprisingly, however, we found that the drug enhanced the peak currents at both higher and lower voltage steps. Since chloroquine showed such biphasic effects on the thymocyte K(+)-channels, and since those effects were voltage dependent, we examined the effects of chloroquine on the activation and the inactivation of the channel currents. We noted that chloroquine shifted both the activation and the inactivation curves toward the hyperpolarizing potential, and that those shifts were more emphasized at lower voltage steps. We conclude that chloroquine facilitates both the activation and the inactivation of Kv1.3-channel currents in thymocytes, and that those effects are voltage dependent.
