Sodium channel inhibitors used as local anesthetics, antiarrhythmics, or antiepileptics typically have the property of use-dependent inhibition, whereby inhibition is enhanced by repetitive channel activation. For targeting pain, Nav1.8 channels are an attractive target because they are prominent in primary pain-sensing neurons, with little or no expression in most other kinds of neurons, and a number of Nav1.8-targeted compounds have been developed. We examined the characteristics of Nav1.8 inhibition by one of the most potent Nav1.8 inhibitors so far described, A-887826, and found that when studied with physiologic resting potentials and physiologic temperatures, inhibition had strong "reverse use dependence", whereby inhibition was relieved by repetitive short depolarizations. This effect was much stronger with A-887826 than with A-803467, another Nav1.8 inhibitor. The use-dependent relief from inhibition was seen in both human Nav1.8 channels studied in a cell line and in native Nav1.8 channels in mouse dorsal root ganglion (DRG) neurons. In native Nav1.8 channels, substantial relief of inhibition occurred during repetitive stimulation by action potential waveforms at 5 Hz, suggesting that the phenomenon is likely important under physiologic conditions. SIGNIFICANCE STATEMENT: Nav1.8 sodium channels are expressed in primary pain-sensing neurons and are a prime current target for new drugs for pain. This work shows that one of the most potent Nav1.8 inhibitors, A-887826, has the unusual property that inhibition is relieved by repeated short depolarizations. This "reverse use dependence" may reduce inhibition during physiological firing and should be selected against in drug development.

01 Sep 2019·EP EuropaceQ2 · MEDICINE

A cellular model of Brugada syndrome with SCN10A variants using human-induced pluripotent stem cell-derived cardiomyocytes

Q2 · MEDICINE

Article

Author: Xu, Qiang ; Akin, Ibrahim ; Huang, Mengying ; Li, Xin ; Liao, Zhenxing ; Müller, Jonas ; Lang, Siegfried ; Utikal, Jochen ; Cyganek, Lukas ; El-Battrawy, Ibrahim ; Kleinsorge, Mandy ; Dinkel, Hendrik ; Diecke, Sebastian ; Lan, Huan ; Zhou, Xiaobo ; Zhong, Rujia ; Wieland, Thomas ; Borggrefe, Martin ; Zimmermann, Wolfram-Hubertus ; Rudic, Boris ; Zhao, Zhihan ; Albers, Sebastian

AbstractAimsBrugada syndrome (BrS) is associated with a pronounced risk to develop sudden cardiac death (SCD). Up to 21% of patients are related to mutations in SCN5A. Studies identified SCN10A as a contributor of BrS. However, the investigation of the human cellular phenotype of BrS in the presence of SCN10A mutations remains lacking. The objective of this study was to establish a cellular model of BrS in presence of SCN10A mutations using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).Methods and resultsDermal fibroblasts obtained from a BrS patient suffering from SCD harbouring the SCN10A double variants (c.3803G>A and c.3749G>A) and three independent healthy control subjects were reprogrammed to hiPSCs. Human-induced pluripotent stem cells were differentiated into cardiomyocytes (hiPSC-CMs).The hiPSC-CMs from the BrS patient showed a significantly reduced peak sodium channel current (INa) and a significantly reduced ATX II (sea anemone toxin, an enhancer of late INa) sensitive as well as A-887826 (a blocker of SCN10A channel) sensitive late sodium channel current (INa) when compared with the healthy control hiPSC-CMs, indicating loss-of-function of sodium channels. Consistent with reduced INa the action potential amplitude and upstroke velocity (Vmax) were significantly reduced, which may contribute to arrhythmogenesis of BrS. Moreover, Ajmaline effects on action potentials were stronger in BrS-hiPSC-CMs than in healthy control cells. This is in agreement with the higher susceptibility of patients to sodium channel blocking drugs in unmasking BrS.ConclusionPatient-specific hiPSC-CMs are able to recapitulate single-cell phenotype features of BrS with SCN10A mutations and may provide novel opportunities to further elucidate the cellular disease mechanism.

01 Apr 2017·Physiological Reports

Acute inflammation reveals GABA_Areceptor-mediated nociception in mouse dorsal root ganglion neurons via PGE₂receptor 4 signaling

Article

Author: Lee, Pa Reum ; Davies, Alexander J. ; Jung, Sung Jun ; Furue, Hidemasa ; Jang, In Jeong ; Kim, Yong Ho ; Akimoto, Nozomi ; Na, Heung Sik ; Oh, Seog Bae ; Back, Seung Keun

Gamma-aminobutyric acid (GABA) depolarizes dorsal root ganglia (DRG) primary afferent neurons through activation of Cl^- permeable GABA_A receptors but the physiologic role of GABA_A receptors in the peripheral terminals of DRG neurons remains unclear. In this study, we investigated the role of peripheral GABA_A receptors in nociception using a mouse model of acute inflammation. In vivo, peripheral administration of the selective GABA_A receptor agonist muscimol evoked spontaneous licking behavior, as well as spinal wide dynamic range (WDR) neuron firing, after pre-conditioning with formalin but had no effect in saline-treated mice. GABA_A receptor-mediated pain behavior after acute formalin treatment was abolished by the GABA_A receptor blocker picrotoxin and cyclooxygenase inhibitor indomethacin. In addition, treatment with prostaglandin E2 (PGE₂) was sufficient to reveal muscimol-induced licking behavior. In vitro, GABA induced sub-threshold depolarization in DRG neurons through GABA_A receptor activation. Both formalin and PGE₂ potentiated GABA-induced Ca²⁺ transients and membrane depolarization in capsaicin-sensitive nociceptive DRG neurons; these effects were blocked by the prostaglandin E2 receptor 4 (EP4) antagonist AH23848 (10 μmol/L). Furthermore, potentiation of GABA responses by PGE₂ was prevented by the selective Na_v1.8 antagonist A887826 (100 nmol/L). Although the function of the Na⁺-K⁺-2Cl^- co-transporter NKCC1 was required to maintain the Cl^- ion gradient in isolated DRG neurons, NKCC1 was not required for GABA_A receptor-mediated nociceptive behavior after acute inflammation. Taken together, these results demonstrate that GABA_A receptors may contribute to the excitation of peripheral sensory neurons in inflammation through a combined effect involving PGE₂-EP4 signaling and Na⁺ channel sensitization.

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Indication	Highest Phase	Country/Location	Organization	Date
Pain	Discovery	US	Abbott Laboratories (Philippines), Inc.	-

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