The comprehensive electrophysiological study of curcuminoids on delayed-rectifier K + currents in insulin-secreting cells

Kuo, Ping Chung; Yang, Chia Jung; Lee, Yu Chi; Chen, Pei Chun; Liu, Yen Chin; Wu, Sheng‐Nan

doi:10.1016/j.ejphar.2017.12.004

Cited by 16 publications

(13 citation statements)

References 41 publications

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“…Nonetheless, the suppression of I h and I K(DR) produced by CIL might concertedly affect the electrical behaviors of endocrine or neuroendocrine cells, which are present in vivo. Indeed, previous studies have demonstrated the presence of I h and I K(DR) in endocrine cells, such as pancreatic αor β-cells [4][5][6]11,39]. The I K(DR) presented herein (i.e., K V 2.1-encoded current) has been reported to be functionally enriched in different types of heart cells [25,26,40,41].…”

Section: Discussionsupporting

confidence: 50%

Inhibitory Effective Perturbations of Cilobradine (DK-AH269), A Blocker of HCN Channels, on the Amplitude and Gating of Both Hyperpolarization-Activated Cation and Delayed-Rectifier Potassium Currents

2020

IJMS

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Cilobradine (CIL, DK-AH269), an inhibitor of hyperpolarization-activated cation current (Ih), has been observed to possess pro-arrhythmic properties. Whether and how CIL is capable of perturbing different types of membrane ionic currents existing in electrically excitable cells, however, is incompletely understood. In this study, we intended to examine possible modifications by it or other structurally similar compounds of ionic currents in pituitary tumor (GH3) cells and in heart-derived H9c2 cells. The standard whole-cell voltage-clamp technique was performed to examine the effect of CIL on ionic currents. GH3-cell exposure to CIL suppressed the density of hyperpolarization-evoked Ih in a concentration-dependent manner with an effective IC50 of 3.38 μM. Apart from its increase in the activation time constant of Ih during long-lasting hyperpolarization, the presence of CIL (3 μM) distinctly shifted the steady-state activation curve of Ih triggered by a 2-s conditioning pulse to a hyperpolarizing direction by 10 mV. As the impedance-frequency relation of Ih was studied, its presence raised the impedance magnitude at the resonance frequency induced by chirp voltage. CIL also suppressed delayed-rectifier K+ current (IK(DR)) followed by the accelerated inactivation time course of this current, with effective IC50 (measured at late IK(DR)) or KD value of 3.54 or 3.77 μM, respectively. As the CIL concentration increased 1 to 3 μM, the inactivation curve of IK(DR) elicited by 1- or 10-s conditioning pulses was shifted to a hyperpolarizing potential by approximately 10 mV, and the recovery of IK(DR) inactivation during its presence was prolonged. The peak Na+ current (INa) during brief depolarization was resistant to being sensitive to the presence of CIL, yet to be either decreased by subsequent addition of A-803467 or enhanced by that of tefluthrin. In cardiac H9c2 cells, unlike the CIL effect, the addition of either ivabradine or zatebradine mildly led to a lowering in IK(DR) amplitude with no conceivable change in the inactivation time course of the current. Taken together, the compound like CIL, which was tailored to block hyperpolarization-activated cation (HCN) channels effectively, was also capable of altering the amplitude and gating of IK(DR), thereby influencing the functional activities of electrically excitable cells, such as GH3 cells.

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Section: Discussionsupporting

confidence: 50%

Inhibitory Effective Perturbations of Cilobradine (DK-AH269), A Blocker of HCN Channels, on the Amplitude and Gating of Both Hyperpolarization-Activated Cation and Delayed-Rectifier Potassium Currents

2020

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“…Aconite alkaloids from Aconitum carmichaelii were recently demonstrated to exert antiviral activity against cucumber mosaic virus ( Xu et al., 2019 ). Additionally, curcuminoids have been demonstrated to depress I K(DR) as well as to fasten I K(DR) inactivation in insulin-secreting cells ( Kuo et al., 2018 ), as well as to possess potent antiviral activities against coronavirus ( Wen et al., 2007 ). Though additional experiments are required to verify the current results, RDV-induced effects on ionic currents demonstrated could be a confounding factor and the notable ionic mechanism underlying its modifications on cell behaviors occurring in vitro or in vivo .…”

Section: Discussionmentioning

confidence: 99%

“…The voltage-gated K + (K V ) channels are essential in determining the membrane excitability in electrically excitable or non-excitable cells. Specifically, K V 3 (KCNC) and K V 2 (KCNB), two delayed-rectifier K + channels, are widespread in different excitable cells such as endocrine cells ( Lien and Jonas, 2003 ; Wang et al., 2008 ; Fletcher et al., 2018 ; Kuo et al., 2018 ; Lu et al., 2019 ; So et al., 2019 ). The causal link between the delayed-rectifier K + current ( I K(DR) ) and K V 3/K V 2 channels has been previously disclosed ( Yeung et al., 2005 ; Wang et al., 2008 ; Huang et al., 2013 ; Chang et al., 2019 ; Lu et al., 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Evidence for the Effectiveness of Remdesivir (GS-5734), a Nucleoside-Analog Antiviral Drug in the Inhibition of IK(M) or IK(DR) and in the Stimulation of IMEP

et al. 2020

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Remdesivir (RDV, GS-5734), a broad-spectrum antiviral drug in the class of nucleotide analogs, has been particularly tailored for treatment of coronavirus infections. However, to which extent RDV is able to modify various types of membrane ion currents remains largely uncertain. In this study, we hence intended to explore the possible perturbations of RDV on ionic currents endogenous in pituitary GH 3 cells and Jurkat T-lymphocytes. The whole-cell current recordings of ours disclosed that upon membrane depolarization in GH 3 cells the exposure to RDV concentration-dependently depressed the peak or late components of I K(DR) elicitation with effective IC 50 values of 10.1 or 2.8 mM, respectively; meanwhile, the value of dissociation constant of RDV-induced blockage of I K(DR) on the basis of the first-order reaction was yielded to be 3.04 mM. Upon the existence of RDV, the steady-state inactivation curve of I K(DR) was established in the RDV presence; moreover, the recovery became slowed. However, RDV-induced blockage of I K(DR) failed to be overcome by further addition of either a,b-methylene ATP or cyclopentyl-1,3dipropylxanthine. The RDV addition also lessened the strength of M-type K + current with the IC 50 value of 2.5 mM. The magnitude of voltage hysteresis of I K(M) elicited by longlasting triangular ramp pulse was diminished by adding RDV. Membrane electroporationinduced current in response to large hyperpolarization was enhanced, with an EC 50 value of 5.8 mM. Likewise, in Jurkat T-lymphocytes, adding RDV declined I K(DR) amplitude concomitantly with the raised rate of current inactivation applied by step depolarization. Therefore, in terms of the RDV molecule, there appears to be an unintended activity of the prodrug on ion channels. Its inhibition of both I K(DR) and I K(M) occurring in a non-genomic

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“…The biophysical or pharmacological properties of Ih observed in GH3 cells may be distinguishable from those in other types of endocrine cells. Previous studies have demonstrated the presence of Ih or delayed-rectifier K + current in pancreatic β-cells [35,36]. INS-1 cells have retained some characteristics of normal pancreatic β-cells [37].…”

Section: Inhibitory Effect Of Croton-03 On Ih In Ins1 Insulin-secretimentioning

confidence: 93%

Characterization of Inhibitory Effectiveness in Hyperpolarization-Activated Cation Currents by a Group of ent-Kaurane-Type Diterpenoids from Croton tonkinensis

Kuo

Liu

et al. 2020

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Croton is an extensive flowering plant genus in the spurge family, Euphorbiaceae. Three croton compounds with the common ent-kaurane skeleton have been purified from Croton tonkinensis. Methods: We examined any modifications of croton components (i.e., croton-01 [ent-18-acetoxy-7α-hydroxykaur-16-en-15-one], croton-02 [ent-7α,14β-dihydroxykaur-16-en-15-one] and croton-03 [ent-1β-acetoxy-7α,14β-dihydroxykaur-16-en-15-one] on either hyperpolarization-activated cation current (Ih) or erg-mediated K+ current identified in pituitary tumor (GH3) cells and in rat insulin-secreting (INS-1) cells via patch-clamp methods. Results: Addition of croton-01, croton-02, or croton-03 effectively and differentially depressed Ih amplitude. Croton-03 (3 μM) shifted the activation curve of Ih to a more negative potential by approximately 11 mV. The voltage-dependent hysteresis of Ih was also diminished by croton-03 administration. Croton-03-induced depression of Ih could not be attenuated by SQ-22536 (10 μM), an inhibitor of adenylate cyclase, but indeed reversed by oxaliplatin (10 μM). The Ih in INS-1 cells was also depressed effectively by croton-03. Conclusion: Our study highlights the evidence that these ent-kaurane diterpenoids might conceivably perturb these ionic currents through which they have high influence on the functional activities of endocrine or neuroendocrine cells.

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The comprehensive electrophysiological study of curcuminoids on delayed-rectifier K + currents in insulin-secreting cells

Cited by 16 publications

References 41 publications

Inhibitory Effective Perturbations of Cilobradine (DK-AH269), A Blocker of HCN Channels, on the Amplitude and Gating of Both Hyperpolarization-Activated Cation and Delayed-Rectifier Potassium Currents

Inhibitory Effective Perturbations of Cilobradine (DK-AH269), A Blocker of HCN Channels, on the Amplitude and Gating of Both Hyperpolarization-Activated Cation and Delayed-Rectifier Potassium Currents

Evidence for the Effectiveness of Remdesivir (GS-5734), a Nucleoside-Analog Antiviral Drug in the Inhibition of IK(M) or IK(DR) and in the Stimulation of IMEP

Characterization of Inhibitory Effectiveness in Hyperpolarization-Activated Cation Currents by a Group of ent-Kaurane-Type Diterpenoids from Croton tonkinensis

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