Mechanisms of BK channel activation by docosahexaenoic acid in rat coronary arterial smooth muscle cells

Ling Ling Qian, Man Qing Sun, Ru Xing Wang, Tong D Lu, Ying Wu, Shi Peng Dang, Xu Tang, Yuan Ji, Xiao Yu Liu, Xiao Xi Zhao, Wen Wang, Qiang Chai, Min Pan, Fu Yi, Dai Min Zhang, Hon Chi Lee

Research output: Contribution to journalArticle

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Abstract

Aim: Docosahexaenoic acid (DHA) is known to activate the vascular large-conductance calcium-activated potassium (BK) channels and has protective effects on the cardiovascular system. However, the underlying mechanisms through which DHA activates BK channels remain unclear. In this study, we determined such mechanisms by examining the effects of different concentrations of DHA on BK channels in freshly isolated rat coronary arterial smooth muscle cells (CASMCs) using patch clamp techniques. Methods and Results: We found that BK channels are the major potassium currents activated by DHA in rat CASMCs and the effects of DHA on BK channels are concentration dependent with a bimodal distribution. At concentrations of < 1 μM, DHA activated whole-cell BK currents with an EC50 of 0.24 ± 0.05 μM and the activation effects were abolished by pre-incubation with SKF525A (10 μM), a cytochrome P450 (CYP) epoxygenase inhibitor, suggesting the role of DHA-epoxide. High concentrations of DHA (1-10 μM) activated whole-cell BK currents with an EC50 of 2.38 ± 0.22 μM and the activation effects were unaltered by pre-incubation with SKF525A. Single channel studies showed that the open probabilities of BK channels were unchanged in the presence of low concentrations of DHA, while significantly increased with high concentrations of DHA. In addition, DHA induced a dose-dependent increase in cytosolic calcium concentrations with an EC50 of 0.037 ± 0.01 μM via phospholipase C (PLC)-inositol triphosphate (IP3)-Ca2+ signal pathway, and inhibition of this pathway reduced DHA-induced BK activation. Conclusion: These results suggest that DHA can activate BK channels by multiple mechanisms. Low concentration DHA-induced BK channel activation is mediated through CYP epoxygenase metabolites, while high concentration DHA can directly activate BK channels. In addition, DHA at low and high concentrations can both activate BK channels by elevated cytosolic calcium through the PLC-IP3-Ca2+ signal pathway.

Original languageEnglish (US)
Article number223
JournalFrontiers in Pharmacology
Volume9
Issue numberMAR
DOIs
StatePublished - Mar 27 2018

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Large-Conductance Calcium-Activated Potassium Channels
Docosahexaenoic Acids
Smooth Muscle Myocytes
Type C Phospholipases
Cytochrome P-450 Enzyme System
Signal Transduction
Calcium
Epoxy Compounds

Keywords

  • BK channel
  • Coronary arterial smooth muscle cells
  • Cytosolic calcium
  • Docosahexaenoic acid
  • PLC-IP3 signal pathway

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Mechanisms of BK channel activation by docosahexaenoic acid in rat coronary arterial smooth muscle cells. / Qian, Ling Ling; Sun, Man Qing; Wang, Ru Xing; Lu, Tong D; Wu, Ying; Dang, Shi Peng; Tang, Xu; Ji, Yuan; Liu, Xiao Yu; Zhao, Xiao Xi; Wang, Wen; Chai, Qiang; Pan, Min; Yi, Fu; Zhang, Dai Min; Lee, Hon Chi.

In: Frontiers in Pharmacology, Vol. 9, No. MAR, 223, 27.03.2018.

Research output: Contribution to journalArticle

Qian, LL, Sun, MQ, Wang, RX, Lu, TD, Wu, Y, Dang, SP, Tang, X, Ji, Y, Liu, XY, Zhao, XX, Wang, W, Chai, Q, Pan, M, Yi, F, Zhang, DM & Lee, HC 2018, 'Mechanisms of BK channel activation by docosahexaenoic acid in rat coronary arterial smooth muscle cells', Frontiers in Pharmacology, vol. 9, no. MAR, 223. https://doi.org/10.3389/fphar.2018.00223
Qian, Ling Ling ; Sun, Man Qing ; Wang, Ru Xing ; Lu, Tong D ; Wu, Ying ; Dang, Shi Peng ; Tang, Xu ; Ji, Yuan ; Liu, Xiao Yu ; Zhao, Xiao Xi ; Wang, Wen ; Chai, Qiang ; Pan, Min ; Yi, Fu ; Zhang, Dai Min ; Lee, Hon Chi. / Mechanisms of BK channel activation by docosahexaenoic acid in rat coronary arterial smooth muscle cells. In: Frontiers in Pharmacology. 2018 ; Vol. 9, No. MAR.
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abstract = "Aim: Docosahexaenoic acid (DHA) is known to activate the vascular large-conductance calcium-activated potassium (BK) channels and has protective effects on the cardiovascular system. However, the underlying mechanisms through which DHA activates BK channels remain unclear. In this study, we determined such mechanisms by examining the effects of different concentrations of DHA on BK channels in freshly isolated rat coronary arterial smooth muscle cells (CASMCs) using patch clamp techniques. Methods and Results: We found that BK channels are the major potassium currents activated by DHA in rat CASMCs and the effects of DHA on BK channels are concentration dependent with a bimodal distribution. At concentrations of < 1 μM, DHA activated whole-cell BK currents with an EC50 of 0.24 ± 0.05 μM and the activation effects were abolished by pre-incubation with SKF525A (10 μM), a cytochrome P450 (CYP) epoxygenase inhibitor, suggesting the role of DHA-epoxide. High concentrations of DHA (1-10 μM) activated whole-cell BK currents with an EC50 of 2.38 ± 0.22 μM and the activation effects were unaltered by pre-incubation with SKF525A. Single channel studies showed that the open probabilities of BK channels were unchanged in the presence of low concentrations of DHA, while significantly increased with high concentrations of DHA. In addition, DHA induced a dose-dependent increase in cytosolic calcium concentrations with an EC50 of 0.037 ± 0.01 μM via phospholipase C (PLC)-inositol triphosphate (IP3)-Ca2+ signal pathway, and inhibition of this pathway reduced DHA-induced BK activation. Conclusion: These results suggest that DHA can activate BK channels by multiple mechanisms. Low concentration DHA-induced BK channel activation is mediated through CYP epoxygenase metabolites, while high concentration DHA can directly activate BK channels. In addition, DHA at low and high concentrations can both activate BK channels by elevated cytosolic calcium through the PLC-IP3-Ca2+ signal pathway.",
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author = "Qian, {Ling Ling} and Sun, {Man Qing} and Wang, {Ru Xing} and Lu, {Tong D} and Ying Wu and Dang, {Shi Peng} and Xu Tang and Yuan Ji and Liu, {Xiao Yu} and Zhao, {Xiao Xi} and Wen Wang and Qiang Chai and Min Pan and Fu Yi and Zhang, {Dai Min} and Lee, {Hon Chi}",
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T1 - Mechanisms of BK channel activation by docosahexaenoic acid in rat coronary arterial smooth muscle cells

AU - Qian, Ling Ling

AU - Sun, Man Qing

AU - Wang, Ru Xing

AU - Lu, Tong D

AU - Wu, Ying

AU - Dang, Shi Peng

AU - Tang, Xu

AU - Ji, Yuan

AU - Liu, Xiao Yu

AU - Zhao, Xiao Xi

AU - Wang, Wen

AU - Chai, Qiang

AU - Pan, Min

AU - Yi, Fu

AU - Zhang, Dai Min

AU - Lee, Hon Chi

PY - 2018/3/27

Y1 - 2018/3/27

N2 - Aim: Docosahexaenoic acid (DHA) is known to activate the vascular large-conductance calcium-activated potassium (BK) channels and has protective effects on the cardiovascular system. However, the underlying mechanisms through which DHA activates BK channels remain unclear. In this study, we determined such mechanisms by examining the effects of different concentrations of DHA on BK channels in freshly isolated rat coronary arterial smooth muscle cells (CASMCs) using patch clamp techniques. Methods and Results: We found that BK channels are the major potassium currents activated by DHA in rat CASMCs and the effects of DHA on BK channels are concentration dependent with a bimodal distribution. At concentrations of < 1 μM, DHA activated whole-cell BK currents with an EC50 of 0.24 ± 0.05 μM and the activation effects were abolished by pre-incubation with SKF525A (10 μM), a cytochrome P450 (CYP) epoxygenase inhibitor, suggesting the role of DHA-epoxide. High concentrations of DHA (1-10 μM) activated whole-cell BK currents with an EC50 of 2.38 ± 0.22 μM and the activation effects were unaltered by pre-incubation with SKF525A. Single channel studies showed that the open probabilities of BK channels were unchanged in the presence of low concentrations of DHA, while significantly increased with high concentrations of DHA. In addition, DHA induced a dose-dependent increase in cytosolic calcium concentrations with an EC50 of 0.037 ± 0.01 μM via phospholipase C (PLC)-inositol triphosphate (IP3)-Ca2+ signal pathway, and inhibition of this pathway reduced DHA-induced BK activation. Conclusion: These results suggest that DHA can activate BK channels by multiple mechanisms. Low concentration DHA-induced BK channel activation is mediated through CYP epoxygenase metabolites, while high concentration DHA can directly activate BK channels. In addition, DHA at low and high concentrations can both activate BK channels by elevated cytosolic calcium through the PLC-IP3-Ca2+ signal pathway.

AB - Aim: Docosahexaenoic acid (DHA) is known to activate the vascular large-conductance calcium-activated potassium (BK) channels and has protective effects on the cardiovascular system. However, the underlying mechanisms through which DHA activates BK channels remain unclear. In this study, we determined such mechanisms by examining the effects of different concentrations of DHA on BK channels in freshly isolated rat coronary arterial smooth muscle cells (CASMCs) using patch clamp techniques. Methods and Results: We found that BK channels are the major potassium currents activated by DHA in rat CASMCs and the effects of DHA on BK channels are concentration dependent with a bimodal distribution. At concentrations of < 1 μM, DHA activated whole-cell BK currents with an EC50 of 0.24 ± 0.05 μM and the activation effects were abolished by pre-incubation with SKF525A (10 μM), a cytochrome P450 (CYP) epoxygenase inhibitor, suggesting the role of DHA-epoxide. High concentrations of DHA (1-10 μM) activated whole-cell BK currents with an EC50 of 2.38 ± 0.22 μM and the activation effects were unaltered by pre-incubation with SKF525A. Single channel studies showed that the open probabilities of BK channels were unchanged in the presence of low concentrations of DHA, while significantly increased with high concentrations of DHA. In addition, DHA induced a dose-dependent increase in cytosolic calcium concentrations with an EC50 of 0.037 ± 0.01 μM via phospholipase C (PLC)-inositol triphosphate (IP3)-Ca2+ signal pathway, and inhibition of this pathway reduced DHA-induced BK activation. Conclusion: These results suggest that DHA can activate BK channels by multiple mechanisms. Low concentration DHA-induced BK channel activation is mediated through CYP epoxygenase metabolites, while high concentration DHA can directly activate BK channels. In addition, DHA at low and high concentrations can both activate BK channels by elevated cytosolic calcium through the PLC-IP3-Ca2+ signal pathway.

KW - BK channel

KW - Coronary arterial smooth muscle cells

KW - Cytosolic calcium

KW - Docosahexaenoic acid

KW - PLC-IP3 signal pathway

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DO - 10.3389/fphar.2018.00223

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JO - Frontiers in Pharmacology

JF - Frontiers in Pharmacology

SN - 1663-9812

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