W-7 inhibits voltage-dependent K+ channels independent of calmodulin activity in rabbit coronary arterial smooth muscle cells

Li, Hongliang; Choi, Il‐Whan; Hong, Da Hye; Son, Youn Kyoung; Na, Sung Hun; Jung, Won‐Kyo; Firth, Amy L.; Jung, In Duk; Park, Yeong‐Min; Park, Won Sun

doi:10.1016/j.ejphar.2014.12.026

Cited by 9 publications

(5 citation statements)

References 36 publications

(49 reference statements)

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“…The strong decrease in intracellular Ca 2ϩ induced by HDAC6i suggests that the reduction in cAMP induced by HDAC6i cannot be the result of Ca 2ϩ regulation of AC6 but most likely occurs via a decrease in AC3 (20). Because the Ca 2ϩ sensitivity of AC3 is modulated by calmodulin (3), we treated the cells with two known inhibitors of calmodulin (W-7 and W-13) to evaluate the role of AC3 (41,42).…”

Section: Hdac6 Inhibition Decreases Camp and Calcium In Adpkdmentioning

confidence: 99%

Histone deacetylase 6 inhibition reduces cysts by decreasing cAMP and Ca2+ in knock-out mouse models of polycystic kidney disease

Yanda

Liu

Cebotaru

et al. 2017

Journal of Biological Chemistry

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Autosomal dominant polycystic kidney disease (ADPKD) is associated with progressive enlargement of multiple renal cysts, often leading to renal failure that cannot be prevented by a current treatment. Two proteins encoded by two genes are associated with ADPKD: PC1 (), primarily a signaling molecule, and PC2 (), a Ca channel. Dysregulation of cAMP signaling is central to ADPKD, but the molecular mechanism is unresolved. Here, we studied the role of histone deacetylase 6 (HDAC6) in regulating cyst growth to test the possibility that inhibiting HDAC6 might help manage ADPKD. Chemical inhibition of HDAC6 reduced cyst growth in PC1-knock-out mice. In proximal tubule-derived, PC1-knock-out cells, adenylyl cyclase 6 and 3 (AC6 and -3) are both expressed. AC6 protein expression was higher in cells lacking PC1, compared with control cells containing PC1. Intracellular Ca was higher in PC1-knock-out cells than in control cells. HDAC inhibition caused a drop in intracellular Ca and increased ATP-simulated Ca release. HDAC6 inhibition reduced the release of Ca from the endoplasmic reticulum induced by thapsigargin, an inhibitor of endoplasmic reticulum Ca-ATPase. HDAC6 inhibition and treatment of cells with the intracellular Ca chelator 1,2-bis(2-aminophenoxy)ethane-,,','-tetraacetic acid tetrakis(acetoxymethyl ester) reduced cAMP levels in PC1-knock-out cells. Finally, the calmodulin inhibitors W-7 and W-13 reduced cAMP levels, and W-7 reduced cyst growth, suggesting that AC3 is involved in cyst growth regulated by HDAC6. We conclude that HDAC6 inhibition reduces cell growth primarily by reducing intracellular cAMP and Ca levels. Our results provide potential therapeutic targets that may be useful as treatments for ADPKD.

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Section: Hdac6 Inhibition Decreases Camp and Calcium In Adpkdmentioning

confidence: 99%

Histone deacetylase 6 inhibition reduces cysts by decreasing cAMP and Ca2+ in knock-out mouse models of polycystic kidney disease

Yanda

Liu

Cebotaru

et al. 2017

Journal of Biological Chemistry

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“…In addition, Ca 2+ channel inhibitors, including verapamil, mibefradil, efonidipine, and NNC 55‐0396, directly inhibit vascular Kv channels independent of Ca 2+ channel inhibition . Calmodulin inhibitors, such as trifluoperazine, W‐7, and CGS 9343B, have also been reported to inhibit the vascular Kv current irrespective of calmodulin inhibition . Our group recently revealed that another SSRI, fluvoxamine, inhibits vascular Kv channels independent of serotonin reuptake inhibition.…”

Section: Discussionmentioning

confidence: 99%

“…[21][22][23][24] Calmodulin inhibitors, such as trifluoperazine, W-7, and CGS 9343B, have also been reported to inhibit the vascular Kv current irrespective of calmodulin inhibition. [25][26][27] Our group recently revealed that another SSRI, fluvoxamine, inhibits vascular Kv channels independent of serotonin reuptake inhibition. Similar to the results obtained using dapoxetine, fluvoxamine shifted the inactivation curves toward a negative potential without altering the activation curves.…”

Section: Discussionmentioning

confidence: 99%

The selective serotonin reuptake inhibitor dapoxetine inhibits voltage‐dependent K⁺ channels in rabbit coronary arterial smooth muscle cells

Kim

et al. 2017

Clin Exp Pharma Physio

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We investigated the inhibitory effect of dapoxetine, a selective serotonin reuptake inhibitor (SSRI), on voltage-dependent K (Kv) channels using native smooth muscle cells from rabbit coronary arteries. Dapoxetine inhibited Kv channel currents in a concentration-dependent manner, with an IC value of 2.68±0.94 μmol/L and a slope value (Hill coefficient) of 0.63±0.11. Application of 10 μmol/L dapoxetine accelerated the rate of inactivation of Kv currents. Although dapoxetine did not modify current activation kinetics, it caused a significant negative shift in the inactivation curves. Application of train step (1 or 2 Hz) progressively increased the inhibitory effect of dapoxetine on Kv channels. In addition, the recovery time constant was extended in its presence, suggesting that the longer recovery time constant from inactivation underlies a use-dependent inhibition of the channel. From these results, we conclude that dapoxetine inhibits Kv channels in a dose-, time-, use-, and state (open)-dependent manner, independent of serotonin reuptake inhibition.

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“…Previous studies have demonstrated that four types of K + channel are expressed in vascular smooth muscle: voltage‐dependent K + (Kv), inwardly rectifying K + (Kir), large‐conductance Ca 2+ ‐activated K + (BK Ca ), and K ATP channels . Although most of the K + channels are at least partially involved in maintaining vascular tone, Kv channels are regarded as one of the most crucial channels in determining the resting membrane potential and thereby the basal tone of the vessel . Kv channels are also strongly regulated by intracellular protein kinases including protein kinase C (PKC), protein kinase A (PKA), and protein kinase G (PKG), which are associated with numerous cellular functions .…”

Section: Introductionmentioning

confidence: 99%

The vasorelaxant effect of antidiabetic drug nateglinide via activation of voltage‐dependent K⁺ channels in aortic smooth muscle

Kim

Shin

et al. 2017

Cardiovascular Therapeutics

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Summary Aims We investigated the vasorelaxant effect of nateglinide and its related mechanisms using phenylephrine (Phe)‐induced precontracted aortic rings. Methods Arterial tone measurement was performed in aortic smooth muscle. Results The application of nateglinide induced vasorelaxation in a concentration‐dependent manner. Pretreatment with the large‐conductance Ca2+‐activated K+ (BKCa) channel inhibitor paxilline, the inwardly rectifying K+ (Kir) channel inhibitor Ba2+, and ATP‐sensitive K+ (KATP) channel inhibitor glibenclamide did not affect the vasorelaxant effect of nateglinide. However, pretreatment with the voltage‐dependent K+ (Kv) channel inhibitor 4‐aminopyridine (4‐AP) effectively reduced the vasorelaxant effect of nateglinide. Pretreatment with the Ca2+ inhibitor nifedipine and the sarcoplasmic/endoplasmic reticulum Ca2+‐ATPase inhibitor thapsigargin did not change the vasorelaxant effect of nateglinide. Additionally, the vasorelaxant effect of nateglinide was not altered in the presence of an adenylyl cyclase, a protein kinase A, a guanylyl cyclase, or a protein kinase G inhibitor. The vasorelaxant effect of nateglinide was not affected by the elimination of the endothelium. In addition, pretreatment with a nitric oxide synthase inhibitor, L‐NAME, and a small‐conductance Ca2+‐activated K+ (SKCa) channel inhibitor, apamin, did not change the vasorelaxant effect of nateglinide. Conclusion Nateglinide induced vasorelaxation via the activation of the Kv channel independent of other K+ channels, Ca2+ channels, intracellular Ca2+ ([Ca2+]i), and the endothelium.

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W-7 inhibits voltage-dependent K+ channels independent of calmodulin activity in rabbit coronary arterial smooth muscle cells

Cited by 9 publications

References 36 publications

Histone deacetylase 6 inhibition reduces cysts by decreasing cAMP and Ca2+ in knock-out mouse models of polycystic kidney disease

Histone deacetylase 6 inhibition reduces cysts by decreasing cAMP and Ca2+ in knock-out mouse models of polycystic kidney disease

The selective serotonin reuptake inhibitor dapoxetine inhibits voltage‐dependent K⁺ channels in rabbit coronary arterial smooth muscle cells

The vasorelaxant effect of antidiabetic drug nateglinide via activation of voltage‐dependent K⁺ channels in aortic smooth muscle

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W-7 inhibits voltage-dependent K+ channels independent of calmodulin activity in rabbit coronary arterial smooth muscle cells

Cited by 9 publications

References 36 publications

Histone deacetylase 6 inhibition reduces cysts by decreasing cAMP and Ca2+ in knock-out mouse models of polycystic kidney disease

Histone deacetylase 6 inhibition reduces cysts by decreasing cAMP and Ca2+ in knock-out mouse models of polycystic kidney disease

The selective serotonin reuptake inhibitor dapoxetine inhibits voltage‐dependent K+ channels in rabbit coronary arterial smooth muscle cells

The vasorelaxant effect of antidiabetic drug nateglinide via activation of voltage‐dependent K+ channels in aortic smooth muscle

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The selective serotonin reuptake inhibitor dapoxetine inhibits voltage‐dependent K⁺ channels in rabbit coronary arterial smooth muscle cells

The vasorelaxant effect of antidiabetic drug nateglinide via activation of voltage‐dependent K⁺ channels in aortic smooth muscle