SK2 channels regulate mitochondrial respiration and mitochondrial Ca2+ uptake

Honrath, Birgit; Matschke, Lina A.; Meyer, Tammo; Magerhans, Lena; Perocchi, Fabiana; Ganjam, Goutham K.; Zischka, Hans; Krasel, Cornelius; Gerding, Albert; Bakker, Barbara M.; Bünemann, Moritz; Strack, Stefan; Decher, Niels; Culmsee, Carsten; Dolga, Amalia M.

doi:10.1038/cdd.2017.2

Cited by 53 publications

(45 citation statements)

References 59 publications

(72 reference statements)

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“…The stimulatory effect of naringenin on mitochondrial potassium channels was further confirmed by respiration measurements of fibroblast cells. It was previously observed that activation of the channel followed by an influx of K + into the mitochondrial matrix results in the stimulation of mitochondrial respiration measured in cells . In our study, in fibroblast cells, naringenin‐stimulated respiration (mitochondrial respiratory activity) and its effect was lowered by the application of channel inhibitors such as 5‐hydroxydecanoic acid, glibenclamide and paxilline.…”

Section: Discussionmentioning

confidence: 52%

Naringenin as an opener of mitochondrial potassium channels in dermal fibroblasts

Kampa

Kicińska

Jarmuszkiewicz

et al. 2019

Experimental Dermatology

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Flavonoids belong to a large group of polyphenolic compounds that are widely present in plants. Certain flavonoids, including naringenin, have cytoprotective properties. Although the antioxidant effect has long been thought to be a crucial factor accounting for the cellular effects of flavonoids, mitochondrial channels have emerged recently as targets for cytoprotective strategies. In the present study, we characterized interactions between naringenin and the mitochondrial potassium (mitoBKCa and mitoKATP) channels recently described in dermal fibroblasts. With the use of the patch‐clamp technique and mitoplasts isolated from primary human dermal fibroblast cells, our study shows that naringenin in micromolar concentrations leads to an increase in mitoBKCa channel activity. The opening probability of the channel decreased from 0.97 in the control conditions (200 μmol/L Ca2+) to 0.06 at a low Ca2+ level (1 μmol/L) and increased to 0.85 after the application of 10 μmol/L naringenin. Additionally, the activity of the mitoKATP channel increased following the application of 10 μmol/L naringenin. To investigate the effects of naringenin on mitochondrial function, the oxygen consumption of dermal fibroblast cells was measured in potassium‐containing media. The addition of naringenin significantly and dose‐dependently increased the respiratory rate from 5.8 ± 0.2 to 14.0 ± 0.6 nmol O2 × min−1 × mg protein−1. Additionally, a Raman spectroscopy analysis of skin penetration indicated that the naringenin was distributed in all skin layers, including the epidermis and dermis. In this study, we demonstrated that a flavonoid, naringenin, can activate two potassium channels present in the inner mitochondrial membrane of dermal fibroblasts.

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Section: Discussionmentioning

confidence: 52%

Naringenin as an opener of mitochondrial potassium channels in dermal fibroblasts

Kampa

Kicińska

Jarmuszkiewicz

et al. 2019

Experimental Dermatology

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“…SK2 channels could cause arrhythmia when they are expressed too much or too little in cardiomyocytes [23]. SK2 channels also participate in the mitochondrial function [24][25][26][27].…”

Section: Discussionmentioning

confidence: 99%

Bupivacaine inhibits a small conductance calcium-activated potassium type 2 channel (SK2) in HEK 293 cells

Chen

Xia

Jin

et al. 2019

Preprint

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Background: Bupivacaine blocks many ion channels in the heart muscle, which could cause severe cardiotoxicity. Small conductance calcium-activated potassium type 2 channels (SK2 channels) are widely distributed in the heart cells and are involved in relevant physiological functions. However, whether bupivacaine can inhibit SK2 channels is still unknown. This study investigated the effect of bupivacaine on SK2 channels. Methods: The SK2 channel gene was transfected into human embryonic kidney 293 cells (HEK-293 cells) with Lipofectamine 2000. The whole-cell patch clamp technique was used to study the effect of bupivacaine on SK2 channels. The inhibitory effect of various concentrations of bupivacaine on SK2 currents exhibited a non-linear relation, and the half-maximal inhibitory concentration (IC50) value was determined. Results: Bupivacaine inhibited the SK2 channels reversibly in a dose-dependent manner. The IC50 value of bupivacaine, ropivacaine and lidocaine on the SK2 current was 133.7, 189.3, and 885.8 µM, respectively. The degree of SK2 current inhibition by bupivacaine was dependent on the intracellular concentration of free calcium. Conclusions: The results of this study suggested a new inhibitory effect of bupivacaine on SK2 channels. Future studies should be concerned with the effects of SK2 on bupivacaine cardiotoxicity. Keywords: Bupivacaine, SK2 channel, inhibition, cardiotoxicity, HEK 293.

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“…Activity of the evolutionarily conserved ATP‐dependent K + channel mitoKATP (Garlid et al ., ; Lefer et al ., ), of BKCa (Frankenreiter et al ., ), of the voltage‐gated channel K v 7.4 (Testai et al ., ) as well as of the SK channels (Dolga et al ., ) has been linked to ischaemic preconditioning, ischaemic postconditioning and cytoprotection in general. For this latter channel, a recent work reveals that a neuroprotective mechanism involves attenuation of [Ca 2+ ] m uptake upon SK channel activation and that respiration and complex I activity upon pharmacological activation or overexpression of mitochondrial K Ca 2.2 (SK2) channels resulted in reduced mitochondrial ROS formation (Honrath et al ., ). However, in general, the exact basis of K + channel openers' cytoprotective effects still remains to be elucidated (for recent reviews, see, e.g.…”

Section: Inner Membrane Ion Channelsmentioning

confidence: 97%

Pharmacological modulation of mitochondrial ion channels

Leanza

Checchetto

Biasutto

et al. 2019

British J Pharmacology

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The field of mitochondrial ion channels has undergone a rapid development during the last three decades, due to the molecular identification of some of the channels residing in the outer and inner membranes. Relevant information about the function of these channels in physiological and pathological settings was gained thanks to genetic models for a few, mitochondria‐specific channels. However, many ion channels have multiple localizations within the cell, hampering a clear‐cut determination of their function by pharmacological means. The present review summarizes our current knowledge about the ins and outs of mitochondrial ion channels, with special focus on the channels that have received much attention in recent years, namely, the voltage‐dependent anion channels, the permeability transition pore (also called mitochondrial megachannel), the mitochondrial calcium uniporter and some of the inner membrane‐located potassium channels. In addition, possible strategies to overcome the difficulties of specifically targeting mitochondrial channels versus their counterparts active in other membranes are discussed, as well as the possibilities of modulating channel function by small peptides that compete for binding with protein interacting partners. Altogether, these promising tools along with large‐scale chemical screenings set up to identify new, specific channel modulators will hopefully allow us to pinpoint the actual function of most mitochondrial ion channels in the near future and to pharmacologically affect important pathologies in which they are involved, such as neurodegeneration, ischaemic damage and cancer. Linked Articles This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc

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SK2 channels regulate mitochondrial respiration and mitochondrial Ca2+ uptake

Cited by 53 publications

References 59 publications

Naringenin as an opener of mitochondrial potassium channels in dermal fibroblasts

Naringenin as an opener of mitochondrial potassium channels in dermal fibroblasts

Bupivacaine inhibits a small conductance calcium-activated potassium type 2 channel (SK2) in HEK 293 cells

Pharmacological modulation of mitochondrial ion channels

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