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Lovastatin blocks Kv1.3 channel in human T cells: a new mechanism to explain its immunomodulatory properties.

Zhao N, Dong Q, Qian C, Li S, Wu QF, Ding D, Li J, Wang BB, Guo KF, Xie JJ, Cheng X, Liao YH, Du YM - Sci Rep (2015)

Bottom Line: However, 30 μM Lovastatin had no apparent effect on KCa current in human T cells.At last, Mevalonate application only partially reversed the inhibition of Lovastatin on IL-2 secretion, and the siRNA against Kv1.3 also partially reduced this inhibitory effect of Lovastatin.In conclusion, Lovastatin can exert immunodulatory properties through the new mechanism of blocking Kv1.3 channel.

View Article: PubMed Central - PubMed

Affiliation: Research Center of Ion Channelopathy, Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.

ABSTRACT
Lovastatin is a member of Statins, which are beneficial in a lot of immunologic cardiovascular diseases and T cell-mediated autoimmune diseases. Kv1.3 channel plays important roles in the activation and proliferation of T cells, and have become attractive target for immune-related disorders. The present study was designed to examine the block effect of Lovastatin on Kv1.3 channel in human T cells, and to clarify its new immunomodulatory mechanism. We found that Lovastatin inhibited Kv1.3 currents in a concentration- and voltage-dependent manner, and the IC50 for peak, end of the pulse was 39.81 ± 5.11, 6.92 ± 0.95 μM, respectively. Lovastatin also accelerated the decay rate of current inactivation and negatively shifted the steady-state inactivation curves concentration-dependently, without affecting the activation curve. However, 30 μM Lovastatin had no apparent effect on KCa current in human T cells. Furthermore, Lovastatin inhibited Ca(2+) influx, T cell proliferation as well as IL-2 production. The activities of NFAT1 and NF-κB p65/50 were down-regulated by Lovastatin, too. At last, Mevalonate application only partially reversed the inhibition of Lovastatin on IL-2 secretion, and the siRNA against Kv1.3 also partially reduced this inhibitory effect of Lovastatin. In conclusion, Lovastatin can exert immunodulatory properties through the new mechanism of blocking Kv1.3 channel.

No MeSH data available.


Related in: MedlinePlus

Interaction of Lovastatin with Kv1.3 Wild-Type and Kv1.3 Mutant Channels.Currents were elicited by 200-ms depolarizing voltage steps from a holding potential of −80 to + 40 mV every 10 s. (A) Representative currents through WT Kv1.3 channel expressed in HEK 293 cells before and after application of 30 μM Lovastatin. (B) Effects of 200 μM internally applied TEA alone and in combination with externally applied 30 μM Lovastatin. (C) Effects of of 20 μM externally applied verapamil alone and in combination with externally applied 30 μM Lovastatin. (D–E) Representative currents through H399A (D) and V417A (E) Kv1.3 mutant channels expressed in HEK 293 cells before and after application of 30 μM Lovastatin. (F) Average inhibition% of Kv1.3 channel currents by 30 μM Lovastatin. (*P < 0.05, ***P < 0.001 vs. WT).
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f3: Interaction of Lovastatin with Kv1.3 Wild-Type and Kv1.3 Mutant Channels.Currents were elicited by 200-ms depolarizing voltage steps from a holding potential of −80 to + 40 mV every 10 s. (A) Representative currents through WT Kv1.3 channel expressed in HEK 293 cells before and after application of 30 μM Lovastatin. (B) Effects of 200 μM internally applied TEA alone and in combination with externally applied 30 μM Lovastatin. (C) Effects of of 20 μM externally applied verapamil alone and in combination with externally applied 30 μM Lovastatin. (D–E) Representative currents through H399A (D) and V417A (E) Kv1.3 mutant channels expressed in HEK 293 cells before and after application of 30 μM Lovastatin. (F) Average inhibition% of Kv1.3 channel currents by 30 μM Lovastatin. (*P < 0.05, ***P < 0.001 vs. WT).

Mentions: Next, we observed the voltage-dependent block effect of Lovastatin on Kv1.3 channel. The current density-voltage relationship curves of the peak and the current end of the pulse, before and after 30 μM Lovastatin application, were shown in Fig. 2A,B, respectively. Lovastatin at 30 μM inhibited the peak and the pulse end current apparently above −40 mV when Kv1.3 channel was open. Then, we calculated the inhibition% of 30 μM Lovastatin on the peak and the pulse end current, which was plotted as a function of the test potentials. The activation curve was present in Fig. 3C, too. From –40 mV to 0 mV, the inhibition percentage of Lovastatin on peak and pulse end current increased sharply from 8.7% and 11.0% to 36.8% and 71.1%, respectively. This voltage range was consistent with the voltage for Kv1.3 channel opening. The inhibition increased to a plateau between +10 mV and +60 mV when the channel was fully activated. This blocking character suggested that Lovastatin may bind to the open state of Kv1.3 channel.


Lovastatin blocks Kv1.3 channel in human T cells: a new mechanism to explain its immunomodulatory properties.

Zhao N, Dong Q, Qian C, Li S, Wu QF, Ding D, Li J, Wang BB, Guo KF, Xie JJ, Cheng X, Liao YH, Du YM - Sci Rep (2015)

Interaction of Lovastatin with Kv1.3 Wild-Type and Kv1.3 Mutant Channels.Currents were elicited by 200-ms depolarizing voltage steps from a holding potential of −80 to + 40 mV every 10 s. (A) Representative currents through WT Kv1.3 channel expressed in HEK 293 cells before and after application of 30 μM Lovastatin. (B) Effects of 200 μM internally applied TEA alone and in combination with externally applied 30 μM Lovastatin. (C) Effects of of 20 μM externally applied verapamil alone and in combination with externally applied 30 μM Lovastatin. (D–E) Representative currents through H399A (D) and V417A (E) Kv1.3 mutant channels expressed in HEK 293 cells before and after application of 30 μM Lovastatin. (F) Average inhibition% of Kv1.3 channel currents by 30 μM Lovastatin. (*P < 0.05, ***P < 0.001 vs. WT).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4663632&req=5

f3: Interaction of Lovastatin with Kv1.3 Wild-Type and Kv1.3 Mutant Channels.Currents were elicited by 200-ms depolarizing voltage steps from a holding potential of −80 to + 40 mV every 10 s. (A) Representative currents through WT Kv1.3 channel expressed in HEK 293 cells before and after application of 30 μM Lovastatin. (B) Effects of 200 μM internally applied TEA alone and in combination with externally applied 30 μM Lovastatin. (C) Effects of of 20 μM externally applied verapamil alone and in combination with externally applied 30 μM Lovastatin. (D–E) Representative currents through H399A (D) and V417A (E) Kv1.3 mutant channels expressed in HEK 293 cells before and after application of 30 μM Lovastatin. (F) Average inhibition% of Kv1.3 channel currents by 30 μM Lovastatin. (*P < 0.05, ***P < 0.001 vs. WT).
Mentions: Next, we observed the voltage-dependent block effect of Lovastatin on Kv1.3 channel. The current density-voltage relationship curves of the peak and the current end of the pulse, before and after 30 μM Lovastatin application, were shown in Fig. 2A,B, respectively. Lovastatin at 30 μM inhibited the peak and the pulse end current apparently above −40 mV when Kv1.3 channel was open. Then, we calculated the inhibition% of 30 μM Lovastatin on the peak and the pulse end current, which was plotted as a function of the test potentials. The activation curve was present in Fig. 3C, too. From –40 mV to 0 mV, the inhibition percentage of Lovastatin on peak and pulse end current increased sharply from 8.7% and 11.0% to 36.8% and 71.1%, respectively. This voltage range was consistent with the voltage for Kv1.3 channel opening. The inhibition increased to a plateau between +10 mV and +60 mV when the channel was fully activated. This blocking character suggested that Lovastatin may bind to the open state of Kv1.3 channel.

Bottom Line: However, 30 μM Lovastatin had no apparent effect on KCa current in human T cells.At last, Mevalonate application only partially reversed the inhibition of Lovastatin on IL-2 secretion, and the siRNA against Kv1.3 also partially reduced this inhibitory effect of Lovastatin.In conclusion, Lovastatin can exert immunodulatory properties through the new mechanism of blocking Kv1.3 channel.

View Article: PubMed Central - PubMed

Affiliation: Research Center of Ion Channelopathy, Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.

ABSTRACT
Lovastatin is a member of Statins, which are beneficial in a lot of immunologic cardiovascular diseases and T cell-mediated autoimmune diseases. Kv1.3 channel plays important roles in the activation and proliferation of T cells, and have become attractive target for immune-related disorders. The present study was designed to examine the block effect of Lovastatin on Kv1.3 channel in human T cells, and to clarify its new immunomodulatory mechanism. We found that Lovastatin inhibited Kv1.3 currents in a concentration- and voltage-dependent manner, and the IC50 for peak, end of the pulse was 39.81 ± 5.11, 6.92 ± 0.95 μM, respectively. Lovastatin also accelerated the decay rate of current inactivation and negatively shifted the steady-state inactivation curves concentration-dependently, without affecting the activation curve. However, 30 μM Lovastatin had no apparent effect on KCa current in human T cells. Furthermore, Lovastatin inhibited Ca(2+) influx, T cell proliferation as well as IL-2 production. The activities of NFAT1 and NF-κB p65/50 were down-regulated by Lovastatin, too. At last, Mevalonate application only partially reversed the inhibition of Lovastatin on IL-2 secretion, and the siRNA against Kv1.3 also partially reduced this inhibitory effect of Lovastatin. In conclusion, Lovastatin can exert immunodulatory properties through the new mechanism of blocking Kv1.3 channel.

No MeSH data available.


Related in: MedlinePlus