Inhibition of Kv4.3 by genistein via a tyrosine phosphorylation-independent mechanism

Kim, Hee Jae; Ahn, Hyo–Suk; Choi, Bok Hee; Hahn, Sang June

doi:10.1152/ajpcell.00031.2010

Cited by 15 publications

(15 citation statements)

References 43 publications

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“…1A. Under control conditions, the Kv4.3 current rose rapidly and was then rapidly inactivated as described previously (Ohya et al, 1997;Ahn et al, 2006;Kim et al, 2011). Ranolazine significantly decreased the peak amplitude of Kv4.3 in a concentration-dependent manner.…”

Section: Resultssupporting

confidence: 67%

Effects of Ranolazine on Cloned Cardiac Kv4.3 Potassium Channels

Kim¹,

Ahn²,

Choi³

et al. 2011

J Pharmacol Exp Ther

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The effects of ranolazine, an antianginal drug, on potassium channel Kv4.3 were examined by using the whole-cell patchclamp technique. Ranolazine inhibited the peak amplitude of Kv4.3 in a reversible, concentration-dependent manner with an IC 50 of 128.31 M. The activation kinetics were not significantly affected by ranolazine at concentrations up to 100 M. Applications of 10 and 30 M ranolazine had no effect on the fast and slow inactivation of Kv4.3. However, at concentrations of 100 and 300 M ranolazine caused a significant decrease in the rate of fast inactivation, and at a concentration of 300 M it caused a significant decrease in the rate of slow inactivation, resulting in a crossover of the current traces during depolarization. The Kv4.3 inhibition by ranolazine increased steeply between Ϫ20 and ϩ20 mV. In the full activation voltage range, however, no voltage-dependent inhibition was found. Ranolazine shifted the voltage dependence of the steady-state inactivation of Kv4.3 in the hyperpolarizing direction in a concentration-dependent manner. The apparent dissociation constant (K i ) for ranolazine for interacting with the inactivated state of Kv4.3 was calculated to be 0.32 M. Ranolazine produced little use-dependent inhibition at frequencies of 1 and 2 Hz. Ranolazine did not affect the time course of recovery from the inactivation of Kv4.3. The results indicated that ranolazine inhibited Kv4.3 and exhibited a low affinity for Kv4.3 channels in the closed state but a much higher affinity for Kv4.3 channels in the inactivated state.

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Section: Resultssupporting

confidence: 67%

Effects of Ranolazine on Cloned Cardiac Kv4.3 Potassium Channels

Kim¹,

Ahn²,

Choi³

et al. 2011

J Pharmacol Exp Ther

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“…Unlike PP2, this role in genistein does not seem connected to its tyrosine kinase inhibitory properties because daidzein, the negative control, shows an even larger effect. Both molecules exert other actions not related to tyrosine phosphorylation, like the inhibition of the N-methyl-Daspartate receptor (Huang et al 2010) or the voltagedependent K + (Kv) 4.3 channel (Kim et al 2011). Soy consumption is high in Asian countries like Japan, and there are several studies related to the effect of isoflavones on the immune system, with either positive or negative outcomes (Sakai and Kogiso 2008).…”

Section: Discussionmentioning

confidence: 99%

Macrophages from elders are more permissive to intracellular multiplication of Mycobacterium tuberculosis

Guerra-Laso

González-García

González-Cortés

et al. 2012

AGE

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The elderly account for a disproportionate share of all tuberculosis cases, and the population ageing may not fully explain this phenomenon. We have performed in vitro infection experiments to investigate whether there is an immunological basis for the apparent susceptibility of elders to tuberculosis. In our infection model, Mycobacterium tuberculosis induces a higher production of interleukin (IL)-6 and reactive oxygen species in macrophages from elders than from younger adults. This response did not prevent, however, an increased multiplication of M. tuberculosis in macrophages from elders as compared with the growth observed within cells from adults. By performing a factorial experiment, we have found that IFN-γ, but not IL-1β, IL-6 or TNF-α, stimulate the macrophages to restrict the multiplication of the bacterium in macrophages from elders. Although monocytes from elders seem to be in a higher level of activation, we present evidences that protein tyrosine phosphorylation response induced by M. tuberculosis is stronger in monocytes from adults than from elders. Using a protein array that detects 71 tyrosine phosphorylated kinases, we identified Pyk2 as the only kinase that displayed a difference of intensity larger than 50 % in adults than in elders. Furthermore, monocytes from elders that were incubated in the presence of tyrosine kinase inhibitors (genistein and PP2) allowed a higher level of bacterial multiplication. These observations may help to explain the susceptibility of elders to tuberculosis. An unexpected result was that both genistein and its negative control, daidzein, abundant soy isoflavones, promoted intracellular mycobacterial growth.

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“…8, D and G). Recent pharmacological studies showed that some compounds can inhibit Kv4.3 function by accelerating channel CSI, suggesting that Kv4 inhibition might result from an increased number of unavailable channels that are in closed inactivated states (41)(42)(43)(44)(45). To test the gating effect of KChIP4a, we co-expressed Kv4.3 with the KChIP4a core (KChIP4a⌬2-34) and found that preferential CSI was reduced (Fig.…”

Section: Kchip4a Suppresses Kv43 Function Via Its N-terminal Kid-mentioning

confidence: 99%

Auxiliary KChIP4a Suppresses A-type K+ Current through Endoplasmic Reticulum (ER) Retention and Promoting Closed-state Inactivation of Kv4 Channels

Tang

Liang

Zhou

et al. 2013

Journal of Biological Chemistry

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Background:Compared with other auxiliary KChIPs that enhance Kv4 current, KChIP4a inhibits Kv4 function. Results: We identified an ER retention motif and an adjacent VKL motif within the KChIP4a N terminus that reduces Kv4.3 surface expression and promotes closed-state inactivation (CSI), respectively. Conclusion: ER retention and CSI enhancement are two distinct mechanisms by which the N terminus of KChIP4a suppresses Kv4 function. Significance: This study provides mechanistic insight into auxiliary KChIP4a-induced inhibition of A-type Kv4 current.

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Inhibition of Kv4.3 by genistein via a tyrosine phosphorylation-independent mechanism

Cited by 15 publications

References 43 publications

Effects of Ranolazine on Cloned Cardiac Kv4.3 Potassium Channels

Effects of Ranolazine on Cloned Cardiac Kv4.3 Potassium Channels

Macrophages from elders are more permissive to intracellular multiplication of Mycobacterium tuberculosis

Auxiliary KChIP4a Suppresses A-type K+ Current through Endoplasmic Reticulum (ER) Retention and Promoting Closed-state Inactivation of Kv4 Channels

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