Blocking effect of methylflavonolamine on human NaV1.5 channels expressed in Xenopus laevis oocytes and on sodium currents in rabbit ventricular myocytes

Fan, Xiaoliang; Ma, Jing; Zhang, Peihua; Xing, Junlian

doi:10.1038/aps.2010.8

Cited by 3 publications

(3 citation statements)

References 20 publications

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“…In the presence of 18β-GA (30 µmol/L), I Na,P of WT Nav1.5 channels did not change after 30 repetitive depolarizing events at 4 Hz (approximately 0.93 at the 30th pulse, n=6 in each group, Figure 4A). On the contrary, lidocaine (100 µmol/L) caused a significant rate-dependent reduction in the current conducted by the WT Nav1.5 channel (P<0.05 at 1 Hz and 2 Hz, P<0.01 at 4 Hz, n=5, Figure 4B), which is similar to other reports [20,21] . The I Na,P mediated by the WT Nav1.5 channel ( Figure 4A) shows that the administration of 18β-GA at 100 µmol/L caused an additional phasic block of I Na,P and I Na,L at ΔKPQ Nav1.5 channels (P<0.05, n=6, Figures 4C and 4D).…”

Section: Wwwchinapharcom Du Ym Et Alsupporting

confidence: 89%

18β-Glycyrrhetinic acid preferentially blocks late Na current generated by ΔKPQ Nav1.5 channels

Xia

Zhao

et al. 2012

Acta Pharmacol Sin

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Aim:To compare the effects of two stereoisomeric forms of glycyrrhetinic acid on different components of Na + current, HERG and Kv1.5 channel currents. Methods: Wild-type (WT) and long QT syndrome type 3 (LQT-3) mutant ∆KPQ Nav1.5 channels, as well as HERG and Kv1.5 channels were expressed in Xenopus oocytes. In addition, isolated human atrial myocytes were used. Two-microelectrode voltage-clamp technique was used to record the voltage-activated currents. Results: Superfusion of 18β-glycyrrhetinic acid (18β-GA, 1-100 μmol/L) blocked both the peak current (I Na,P ) and late current (I Na,L ) generated by WT and ΔKPQ Nav1.5 channels in a concentration-dependent manner, while 18α-glycyrrhetinic acid (18α-GA) at the same concentrations had no effects. 18β-GA preferentially blocked I Na,L (IC 50 =37.2±14.4 μmol/L) to I Na,P (IC 50 =100.4±11.2 μmol/L) generated by ∆KPQ Nav1.5 channels. In human atrial myocytes, 18β-GA (30 μmol/L) inhibited 47% of I Na,P and 87% of I Na,L induced by Anemonia sulcata toxin (ATX-II, 30 nmol/L). Superfusion of 18β-GA (100 μmol/L) had no effects on HERG and Kv1.5 channel currents. Conclusion: 18β-GA preferentially blocked the late Na current without affecting HERG and Kv1.5 channels.

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Section: Wwwchinapharcom Du Ym Et Alsupporting

confidence: 89%

18β-Glycyrrhetinic acid preferentially blocks late Na current generated by ΔKPQ Nav1.5 channels

Xia

Zhao

et al. 2012

Acta Pharmacol Sin

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“…This effect can be explained by its interaction with S4 segments of domains III and IV [33]. Positive shift of V 1/2 of activation by lidocaine has already been reported for mammalian Na v 1.5 and Na v 1.8, but not for Na v 1.7 [34], [35]. Besides, phasic block by lidocaine is explained by preferential binding to inactivated state of Na v channels [18].…”

Section: Discussionmentioning

confidence: 76%

Intron Retention in mRNA Encoding Ancillary Subunit of Insect Voltage-Gated Sodium Channel Modulates Channel Expression, Gating Regulation and Drug Sensitivity

Bourdin

Moignot²,

Wang³

et al. 2013

PLoS ONE

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Insect voltage-gated sodium (Nav) channels are formed by a well-known pore-forming α-subunit encoded by para-like gene and ancillary subunits related to TipE from the mutation “temperature-induced-paralysis locus E.” The role of these ancillary subunits in the modulation of biophysical and pharmacological properties of Na+ currents are not enough documented. The unique neuronal ancillary subunit TipE-homologous protein 1 of Drosophila melanogaster (DmTEH1) strongly enhances the expression of insect Nav channels when heterologously expressed in Xenopus oocytes. Here we report the cloning and functional expression of two neuronal DmTEH1-homologs of the cockroach, Periplaneta americana, PaTEH1A and PaTEH1B, encoded by a single bicistronic gene. In PaTEH1B, the second exon encoding the last 11-amino-acid residues of PaTEH1A is shifted to 3′UTR by the retention of a 96-bp intron-containing coding-message, thus generating a new C-terminal end. We investigated the gating and pharmacological properties of the Drosophila Nav channel variant (DmNav1-1) co-expressed with DmTEH1, PaTEH1A, PaTEH1B or a truncated mutant PaTEH1Δ(270-280) in Xenopus oocytes. PaTEH1B caused a 2.2-fold current density decrease, concomitant with an equivalent α-subunit incorporation decrease in the plasma membrane, compared to PaTEH1A and PaTEH1Δ(270-280). PaTEH1B positively shifted the voltage-dependences of activation and slow inactivation of DmNav1-1 channels to more positive potentials compared to PaTEH1A, suggesting that the C-terminal end of both proteins may influence the function of the voltage-sensor and the pore of Nav channel. Interestingly, our findings showed that the sensitivity of DmNav1-1 channels to lidocaine and to the pyrazoline-type insecticide metabolite DCJW depends on associated TEH1-like subunits. In conclusion, our work demonstrates for the first time that density, gating and pharmacological properties of Nav channels expressed in Xenopus oocytes can be modulated by an intron retention process in the transcription of the neuronal TEH1-like ancillary subunits of P. americana.

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“…The concentration of 3 µM was chosen because it gave rise to a considerable amount of changes in NaV1.5 current in voltage clamp experiments on HEK-293 cells (Figures 1-3) without too extreme effects that might prevent excitability of cardiomyocytes completely. Figure 4a shows typical AP recordings Many NaV1.5 current inhibitors-including, for example, methylflavonolamine and lidocaine [36], hesperetin [37], eleclazine [38], carbamazepine [39], mexiletine [40], and aripiprazole [41]-generate a shift in steady-state inactivation to more negative potentials (as shown for paroxetine in Figure 2c,d) that is accompanied by a slowing of recovery from inactivation. Under close-to-physiological conditions, i.e., at a potential of −85 mV and 37 °C [35], recovery from inactivation of the sodium current in cardiomyocytes is not fully complete within 1 s, which explains why the maximum AP upstroke velocity at a pacing frequency of 3 Hz is smaller than at 1 Hz under control conditions (Figure 5a, gray lines; Figure 5b, gray bars).…”

Section: Effects Of Paroxetine On Action Potentials Of Rabbit Left Ve...mentioning

confidence: 99%

The Antidepressant Paroxetine Reduces the Cardiac Sodium Current

Plijter

Verkerk

Wilders

2023

IJMS

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A considerable amount of literature has been published on antidepressants and cardiac ion channel dysfunction. The antidepressant paroxetine has been associated with Brugada syndrome and long QT syndrome, albeit on the basis of conflicting findings. The cardiac voltage-gated sodium channel (NaV1.5) is related to both of these syndromes, suggesting that paroxetine may have an effect on this channel. In the present study, we therefore carried out patch clamp experiments to examine the effect of paroxetine on human NaV1.5 channels stably expressed in human embryonic kidney 293 (HEK-293) cells as well as on action potentials of isolated rabbit left ventricular cardiomyocytes. Additionally, computer simulations were conducted to test the functional effects of the experimentally observed paroxetine-induced changes in the NaV1.5 current. We found that paroxetine led to a decrease in peak NaV1.5 current in a concentration-dependent manner with an IC50 of 6.8 ± 1.1 µM. In addition, paroxetine caused a significant hyperpolarizing shift in the steady-state inactivation of the NaV1.5 current as well as a significant increase in its rate of inactivation. Paroxetine (3 µM) affected the action potential of the left ventricular cardiomyocytes, significantly decreasing its maximum upstroke velocity and amplitude, both of which are mainly regulated by the NaV1.5 current. Our computer simulations demonstrated that paroxetine substantially reduces the fast sodium current of human left ventricular cardiomyocytes, thereby slowing conduction and reducing excitability in strands of cells, in particular if conduction and excitability are already inhibited by a loss-of-function mutation in the NaV1.5 encoding SCN5A gene. In conclusion, paroxetine acts as an inhibitor of NaV1.5 channels, which may enhance the effects of loss-of-function mutations in SCN5A.

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Blocking effect of methylflavonolamine on human NaV1.5 channels expressed in Xenopus laevis oocytes and on sodium currents in rabbit ventricular myocytes

Cited by 3 publications

References 20 publications

18β-Glycyrrhetinic acid preferentially blocks late Na current generated by ΔKPQ Nav1.5 channels

18β-Glycyrrhetinic acid preferentially blocks late Na current generated by ΔKPQ Nav1.5 channels

Intron Retention in mRNA Encoding Ancillary Subunit of Insect Voltage-Gated Sodium Channel Modulates Channel Expression, Gating Regulation and Drug Sensitivity

The Antidepressant Paroxetine Reduces the Cardiac Sodium Current

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