Control of somatic membrane potential in nociceptive neurons and its implications for peripheral nociceptive transmission

Du, Xiaona; Hao, Han; Gigout, Sylvain; Huang, Dongyang; Yang, Yuehui; Li, L i; Wang, Caixue; Sundt, Danielle; Jaffe, David B.; Zhang, Hailin; Gamper, Nikita

doi:10.1016/j.pain.2014.08.025

Cited by 115 publications

(172 citation statements)

References 123 publications

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“…These computer simulations in combination with our experimental findings in DRG neurons and on isolated M-channels suggest that PUFA-induced augmentation of the M-current contributes to the anti-excitable effect of PUFAs. This is further supported by a comparison of the PUFA effects found in the present work and previously reported effects of the clinically approved M-channel opener retigabine; the PUFA effects on the resting membrane potential and the firing threshold in DRG neurons, and on the voltage dependence of the isolated human M-channel expressed in Xenopus oocytes are, on the whole, similar to, but quantitatively smaller than, the effect of retigabine (Main et al 2000;Zheng et al 2013;Du et al 2014). Our finding that DHA methyl ester and oleic acid were ineffective suggests that possible anti-excitable effects of PUFA methyl esters and monounsaturated fatty acids are not mediated via the M-channel.…”

Section: Discussionsupporting

confidence: 89%

Polyunsaturated fatty acids are potent openers of human M‐channels expressed in Xenopus laevis oocytes

et al. 2016

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Methods: Effects of fatty acids and fatty-acid analogues on mouse dorsal root ganglion neurons and on the human K V 7.2/3 channel expressed in Xenopus laevis oocytes were studied using electrophysiology. Conclusions: These findings suggest that circulating polyunsaturated fatty acids, with a minimum requirement of multiple double bonds and a charged carboxyl group, dampen excitability by opening neuronal M-channels. Collectively, our data bring light to the molecular targets of polyunsaturated fatty acids and thus a possible mechanism by which polyunsaturated fatty acids reduce neuronal excitability. Results

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Section: Discussionsupporting

confidence: 89%

Polyunsaturated fatty acids are potent openers of human M‐channels expressed in Xenopus laevis oocytes

et al. 2016

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“…M channels are expressed in mammalian somatosensory neurons (especially in pain or nociceptive neurons) and are important for the control of their resting excitability (29,30), ultimately controlling nociceptive signaling (reviewed in ref. 31).…”

Section: Resultsmentioning

confidence: 99%

Intracellular zinc activates KCNQ channels by reducing their dependence on phosphatidylinositol 4,5-bisphosphate

Gao

Boillat

Huang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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M-type (Kv7, KCNQ) potassium channels are proteins that control the excitability of neurons and muscle cells. Many physiological and pathological mechanisms of excitation operate via the suppression of M channel activity or expression. Conversely, pharmacological augmentation of M channel activity is a recognized strategy for the treatment of hyperexcitability disorders such as pain and epilepsy. However, physiological mechanisms resulting in M channel potentiation are rare. Here we report that intracellular free zinc directly and reversibly augments the activity of recombinant and native M channels. This effect is mechanistically distinct from the known redoxdependent KCNQ channel potentiation. Interestingly, the effect of zinc cannot be attributed to a single histidine-or cysteine-containing zinc-binding site within KCNQ channels. Instead, zinc dramatically reduces KCNQ channel dependence on its obligatory physiological activator, phosphatidylinositol 4,5-bisphosphate (PIP 2 ). We hypothesize that zinc facilitates interactions of the lipid-facing interface of a KCNQ protein with the inner leaflet of the plasma membrane in a way similar to that promoted by PIP 2 . Because zinc is increasingly recognized as a ubiquitous intracellular second messenger, this discovery might represent a hitherto unknown native pathway of M channel modulation and provide a fresh strategy for the design of M channel activators for therapeutic purposes.+ channels are a family of voltagegated K + channels with a very distinctive and robust role in the control of cellular excitability. The channels give rise to noninactivating K + currents with slow kinetics and a very negative activation threshold (−60 mV or even more negative). In combination, these features allow KCNQ channels to remain partially active at voltages near the resting membrane potential of a neuron or a muscle cell and thus strongly influence excitability (1, 2). Transient KCNQ channel inhibition leads to reversible increases in neuronal excitability, whereas long-term losses of KCNQ channel activity often result in debilitating excitability disorders (1, 2). Thus, loss-of-function mutations within KCNQ genes underlie some types of epilepsy, deafness, and arrhythmias, whereas transcriptional down-regulation in sensory nerves may result in chronic pain (2). Conversely, M channel enhancers ("openers") reduce excitability and are clinically used as antiepileptic drugs (e.g., retigabine) or analgesics (e.g., flupirtine) (3). The therapeutic utility of KCNQ channel openers extends to other disorders linked to deregulated excitability, such as anxiety, stroke, and smooth muscle disorders (2, 3); therefore a global quest for specific and selective KCNQ openers is currently underway (3).The KCNQ channel family contains five members, KCNQ1-5 (Kv7.1-Kv7.5). KCNQ1 is expressed mostly within the cardiovascular system, whereas the other members are predominantly neuronal (1, 2). The most abundant M-type channel within the nervous system is believed to be the heteromeric KCNQ2/3 chan...

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“…DRG neurons were cultured as described previously [22,23,24]. Briefly, adult Sprague Dawley rats (170 g-180 g) were humanly euthanized by isoflurane overdose.…”

Section: Methodsmentioning

confidence: 99%

“…Briefly, adult Sprague Dawley rats (170 g-180 g) were humanly euthanized by isoflurane overdose. DRGs from all spinal levels were extracted and dissociated using collagenase/dispase method as described [22,23,24]. Dissociated cells we cultured in DMEN supplemented with GlutaMax I, 10 % fetal calf serum, penicillin (50 U/ml) and streptomycin (50 g/ml) on glass coverslips coated with poly-D-lysine for 2-5 days in a humidified incubator (37°C, 5% CO2).…”

Section: Methodsmentioning

confidence: 99%

GABAB receptors inhibit low-voltage activated and high-voltage activated Ca2+ channels in sensory neurons via distinct mechanisms

Huang

Peers

et al. 2015

Biochemical and Biophysical Research Communications

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Abbreviations: DRG, dorsal root ganglion; DTT, dithiothreitol; GABA, gamma-aminobutyric acid; GFP, green fluorescent protein; HEK293, human embryonic kidney 293 cells; HVA, high voltage activated Ca 2+ channels; LVA, low voltage activated Ca 2+ channels; NK1, neurokinin receptor isoform 1; ROS, reactive oxygen species; PTX, pertussis toxin; VGCC, voltage-gated Ca 2+ channels Abstract Growing evidence suggests that mammalian peripheral somatosensory neurons express functional receptors for gamma-aminobutyric acid, GABAA and GABAB. Moreover, local release of GABA by pain-sensing (nociceptive) nerve fibres has also been suggested. Yet, the functional significance of GABA receptor triggering in nociceptive neurons is not fully understood. Here we used patchclamp recordings from small-diameter cultured DRG neurons to investigate effects of GABAB receptor agonist baclofen on voltage-gated Ca 2+ currents. We found that baclofen inhibited both low-voltage activated (LVA, T-type) and high-voltage activated (HVA) Ca 2+ currents in a proportion of DRG neurons by 22% and 32% respectively; both effects were sensitive to Gi/o inhibitor pertussis toxin. Inhibitory effect of baclofen on both current types was about twice less efficacious as compared to that of the -opioid receptor agonist DAMGO. Surprisingly, only HVA but not LVA current modulation by baclofen was partially prevented by G protein inhibitor GDP--S. In contrast, only LVA but not HVA current modulation was reversed by the application of a reducing agent dithiothreitol (DTT). Inhibition of T-type Ca 2+ current by baclofen and the recovery of such inhibition by DTT were successfully reconstituted in the expression system. Our data suggest that inhibition of LVA current in DRG neurons by baclofen is partially mediated by an unconventional signaling pathway that involves a redox mechanism. These findings reinforce the idea of targeting peripheral GABA receptors for pain relief.

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Control of somatic membrane potential in nociceptive neurons and its implications for peripheral nociceptive transmission

Abstract: SummaryWe identified major ion channels influencing the resting membrane potential of nociceptive sensory neurons and demonstrated that changes of somatic/perisomatic membrane potential of these neurons can strongly influence peripheral nociceptive transmission.

Cited by 115 publications

References 123 publications

Polyunsaturated fatty acids are potent openers of human M‐channels expressed in Xenopus laevis oocytes

Polyunsaturated fatty acids are potent openers of human M‐channels expressed in Xenopus laevis oocytes

Intracellular zinc activates KCNQ channels by reducing their dependence on phosphatidylinositol 4,5-bisphosphate

GABAB receptors inhibit low-voltage activated and high-voltage activated Ca2+ channels in sensory neurons via distinct mechanisms

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