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Differential effects of clarithromycin and azithromycin on delayed rectifier K(+)-channel currents in murine
Itsuro Kazama1, Yoshio Maruyama
1Department of Physiology I, Tohoku University Graduate School of Medicine, Miyagi, Japan. kazaitsu@med.tohoku.ac.jp
Insights
Clarithromycin inhibits potassium channel Kv1.3 currents in lymphocytes, while azithromycin affects membrane capacitance. These distinct effects of macrolide antibiotics may influence their immunomodulatory mechanisms.
Area of Science:
- Immunology
- Cell Physiology
- Pharmacology
Background:
- Lymphocytes express delayed rectifier K(+)-channels (Kv1.3) crucial for activation and proliferation.
- Macrolide antibiotics like clarithromycin and azithromycin possess immunomodulatory effects, potentially impacting Kv1.3 channels.
Purpose of the Study:
- To investigate the physiological mechanisms underlying the immunomodulatory effects of clarithromycin and azithromycin.
- To determine how these macrolide antibiotics affect Kv1.3 channel currents and membrane capacitance in lymphocytes.
Main Methods:
- Utilized patch-clamp whole-cell recording technique in murine thymocytes.
- Examined the effects of 30 and 100 µM clarithromycin and azithromycin on Kv1.3 channel currents and membrane capacitance.
Main Results:
- Clarithromycin significantly suppressed peak and pulse-end Kv1.3 channel currents in thymocytes without altering membrane capacitance.
- Azithromycin did not affect Kv1.3 channel currents but significantly decreased membrane capacitance, suggesting plasma membrane accumulation.
Conclusions:
- Clarithromycin inhibits thymocyte Kv1.3 channel currents, while azithromycin decreases membrane capacitance.
- The differing effects of these macrolide antibiotics on lymphocyte ion channels and membrane properties may underlie their distinct immunomodulatory actions and cytokine production control.
Context:
Lymphocytes predominantly express delayed rectifier K(+)-channels (Kv1.3) in their plasma membranes, and the channels play crucial roles in the lymphocyte activation and proliferation. Since macrolide antibiotics, such as clarithromycin and azithromycin, exert immunomodulatory effects, they would affect the Kv1.3-channel currents in lymphocytes.
Objective:
This study determined the physiological involvement in the mechanisms of immunomodulation by these antibiotics.
Materials And Methods:
Employing the standard patch-clamp whole-cell recording technique in murine thymocytes, we examined the effects of 30 and 100 µM clarithromycin and azithromycin on the Kv1.3-channel currents and the membrane capacitance.
Results:
Clarithromycin significantly suppressed the peak currents (30 µM, 178 ± 5.6 to 111 ± 2.0 pA/pF; 100 µM, 277 ± 4.4 to 89.6 ± 10 pA/pF) and the pulse-end currents (30 µM, 47.5 ± 2.2% to 15.5 ± 3.3%; 100 µM, 48.5 ± 1.4% to 15.8 ± 1.0%) of thymocyte Kv1.3-channels without significant effects on the membrane capacitance. In contrast, azithromycin did not affect the channel currents. However, it significantly decreased the membrane capacitance (30 µM, 4.68 ± 0.14 to 3.74 ± 0.13 pF; 100 µM, 4.47 ± 0.06 to 3.37 ± 0.08 pF), indicating its accumulation in the plasma membrane.
Discussion And Conclusion:
This study demonstrated for the first time that clarithromycin exerts inhibitory effects on thymocyte Kv1.3-channel currents, while azithromycin decreases the membrane capacitance without affecting the channel currents. These differences in the effects of the macrolide antibiotics may reflect differences in the mechanisms of immunomodulation by which they control the production of cytokines.
