Downregulation of ClC-3 in dorsal root ganglia neurons contributes to mechanical hypersensitivity following peripheral nerve injury

Pang, Rui‐Ping; Xie, Man-Xiu; Yang, Jie; Shen, Kai-Feng; Chen, Xi; Su, Ying-Xue; Yang, Chia-Han; Tao, Jin‐Hui; Liang, Shi-Dong; Zhou, Jia‐Guo; Zhu, He-Quan; Wei, Xu-Hong; Li, Yongyong; Qin, Zhihai; Liu, Xianguo

doi:10.1016/j.neuropharm.2016.07.023

Cited by 15 publications

(26 citation statements)

References 34 publications

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“…S1P signaling has been known to be involved in many types of pain, e.g., inflammatory pain (Lai et al, 2008 ; Mair et al, 2011 ), postsurgical pain (Camprubí-Robles et al, 2013 ), cancer-induced bone pain (Grenald et al, 2017 ) and chemotherapy-induced neuropathic pain (Janes et al, 2014 ). However, to date, only few studies address the involvement of CLCN channels in pain initiation/modulation (Poët et al, 2006 ; Bali et al, 2013 ; Pang et al, 2016 ). The present study links the chloride channels CLCN3 and CLCN5 with the excitatory role of S1P on sensory neurons and for the first time positions CLCN5 channel, which has been well studied in Dent’s disease, an inherited renal disorder characterized by hyperphosphaturia, proteinuria, hypercalciuria and the development of kidney stones, which is often associated with mutations in the CLCN5 gene (Gunther et al, 2003 ), in the field of nociception and the pain pathway.…”

Section: Discussionmentioning

confidence: 99%

Identification of Chloride Channels CLCN3 and CLCN5 Mediating the Excitatory Cl− Currents Activated by Sphingosine-1-Phosphate in Sensory Neurons

Mair

Kummer

et al. 2018

Front. Mol. Neurosci.

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Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid involved in numerous physiological and pathophysiological processes. We have previously reported a S1P-induced nocifensive response in mice by excitation of sensory neurons via activation of an excitatory chloride current. The underlying molecular mechanism for the S1P-induced chloride conductance remains elusive. In the present study, we identified two CLCN voltage-gated chloride channels, CLCN3 and CLCN5, which mediated a S1P-induced excitatory Cl− current in sensory neurons by combining RNA-seq, adenovirus-based gene silencing and whole-cell electrophysiological voltage-clamp recordings. Downregulation of CLCN3 and CLCN5 channels by adenovirus-mediated delivery of shRNA dramatically reduced S1P-induced Cl− current and membrane depolarization in sensory neurons. The mechanism of S1P-induced activation of the chloride current involved Rho GTPase but not Rho-associated protein kinase. Although S1P-induced potentiation of TRPV1-mediated ionic currents also involved Rho-dependent process, the lack of correlation of the S1P-activated Cl− current and the potentiation of TRPV1 by S1P suggests that CLCN3 and CLCN5 are necessary components for S1P-induced excitatory Cl− currents but not for the amplification of TRPV1-mediated currents in sensory neurons. This study provides a novel mechanistic insight into the importance of bioactive sphingolipids in nociception.

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Section: Discussionmentioning

confidence: 99%

Identification of Chloride Channels CLCN3 and CLCN5 Mediating the Excitatory Cl− Currents Activated by Sphingosine-1-Phosphate in Sensory Neurons

Mair

Kummer

et al. 2018

Front. Mol. Neurosci.

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“…Some members (CLC-2, CLC-3, CLC-5, and CLC-7) are widely expressed whereas others exhibit strict tissue-specific expression (Jentsch et al, 2005;Jentsch and Pusch, 2018). Lumbar DRGs of mice express mRNA transcripts encoding CLC-3, CLC-4, CLC-5, and CLC-6 (Qi et al, 2018) and protein expression in DRGs is demonstrated for CLC-3 and CLC-6 (Poet et al, 2006;Pang et al, 2016). Only few studies address the importance of CLC proteins in the peripheral nervous system, but these demonstrate that CLC proteins are utterly important for determining excitability of DRG neurons under (patho)physiological conditions.…”

Section: Chloride Channel Accessory (Clca)mentioning

confidence: 99%

Section: Clc-3 and Clc-5mentioning

confidence: 99%

“…CLC-3 is expressed in both isolectin-B4-binding (IB4) nonpeptidergic, and peptidergic nociceptors (Bali et al, 2013;Pang et al, 2016). Although resting membrane potentials and voltagedependent currents are unaltered after knockout or knockdown of CLC-3 and CLC-5, ablation of CLC-3 increases the excitability of DRG neurons as indicated by decreased AP thresholds and decreased rheobase (Pang et al, 2016;Qi et al, 2018). This is in line with the hypersensitivity to mechanical sensory stimulation in neuropathic and tumor pain models in rodents with a knockdown or genetic knockout of CLC-3 (Bali et al, 2013;Pang et al, 2016).…”

Section: Clc-3 and Clc-5mentioning

confidence: 99%

“…Although resting membrane potentials and voltagedependent currents are unaltered after knockout or knockdown of CLC-3 and CLC-5, ablation of CLC-3 increases the excitability of DRG neurons as indicated by decreased AP thresholds and decreased rheobase (Pang et al, 2016;Qi et al, 2018). This is in line with the hypersensitivity to mechanical sensory stimulation in neuropathic and tumor pain models in rodents with a knockdown or genetic knockout of CLC-3 (Bali et al, 2013;Pang et al, 2016). Furthermore, CLC-3 and CLC-5 are involved in the downstream signaling of the biologically active sphingolipid S1P (Pang et al, 2016;Qi et al, 2018).…”

Section: Clc-3 and Clc-5mentioning

confidence: 99%

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Chloride – The Underrated Ion in Nociceptors

et al. 2020

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In contrast to pain processing neurons in the spinal cord, where the importance of chloride conductances is already well established, chloride homeostasis in primary afferent neurons has received less attention. Sensory neurons maintain high intracellular chloride concentrations through balanced activity of Na +-K +-2Cl − cotransporter 1 (NKCC1) and K +-Cl − cotransporter 2 (KCC2). Whereas in other cell types activation of chloride conductances causes hyperpolarization, activation of the same conductances in primary afferent neurons may lead to inhibitory or excitatory depolarization depending on the actual chloride reversal potential and the total amount of chloride efflux during channel or transporter activation. Dorsal root ganglion (DRG) neurons express a multitude of chloride channel types belonging to different channel families, such as ligand-gated, ionotropic γ-aminobutyric acid (GABA) or glycine receptors, Ca 2+-activated chloride channels of the anoctamin/TMEM16, bestrophin or tweetyhomolog family, CLC chloride channels and transporters, cystic fibrosis transmembrane conductance regulator (CFTR) as well as volume-regulated anion channels (VRACs). Specific chloride conductances are involved in signal transduction and amplification at the peripheral nerve terminal, contribute to excitability and action potential generation of sensory neurons, or crucially shape synaptic transmission in the spinal dorsal horn. In addition, chloride channels can be modified by a plethora of inflammatory mediators affecting them directly, via protein-protein interaction, or through signaling cascades. Since chloride channels as well as mediators that modulate chloride fluxes are regulated in pain disorders and contribute to nociceptor excitation and sensitization it is timely and important to emphasize their critical role in nociceptive primary afferents in this review.

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Modulatory effects of bufalin, an active ingredient from toad venom on voltage-gated sodium channels

et al. 2018

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Chan-su (toad venom) has been used as an analgesic agent in China from ancient to modern times. Bufalin, a non-peptide toxin extracted from toad venom, is considered as one of the analgesic components. The molecular mechanism underlying the anti-nociceptive effects of bufalin remains unclear so far. In this study, we investigated the pharmacological effects of bufalin on pain-related ion channels as well as animal models through patch clamping, calcium imaging and animal behavior observation. Using the whole-cell recording, bufalin caused remarkable suppressive effect on the peak currents of Nav channels (voltage gated sodium channels, VGSCs) of dorsal root ganglion neuroblastomas (ND7-23 cell) in a dose-dependent manner. Bufalin facilitated the voltage-dependent activation and induced a negative shift on the fast inactivation of VGSCs. The recovery kinetics of VGSCs were significantly slowed and the recovery proportion were reduced after administering bufalin. However, bufalin prompted no significant effect not only on Kv4.2, Kv4.3 and BK channels heterologously expressed in HEK293T cells, but also on the capsaicin and allyl isothiocyanate induced Ca influx. What's more, bufalin could observably relieve formalin-induced spontaneous flinching and licking response as well as carrageenan-induced thermal and mechanical hyperalgesia in dose-dependent manner in agreement with the results of in vitro experiments. The present results imply that the remarkable anti-nociceptive effects produced by bufalin are probably ascribed to its specific regulation on Nav channels. Bufalin inhibits the Nav channels in a dose-dependent manner, which will provide references for the optimal dose selection of analgesia drugs.

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Downregulation of ClC-3 in dorsal root ganglia neurons contributes to mechanical hypersensitivity following peripheral nerve injury

Cited by 15 publications

References 34 publications

Identification of Chloride Channels CLCN3 and CLCN5 Mediating the Excitatory Cl− Currents Activated by Sphingosine-1-Phosphate in Sensory Neurons

Identification of Chloride Channels CLCN3 and CLCN5 Mediating the Excitatory Cl− Currents Activated by Sphingosine-1-Phosphate in Sensory Neurons

Chloride – The Underrated Ion in Nociceptors

Modulatory effects of bufalin, an active ingredient from toad venom on voltage-gated sodium channels

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