N-Methyl-d-aspartate Receptor- and Calpain-mediated Proteolytic Cleavage of K+-Cl− Cotransporter-2 Impairs Spinal Chloride Homeostasis in Neuropathic Pain

Zhou, Hong; Chen, Shao Rui; Byun, Hee Sun; Chen, Hong; Li, Li; Han, Hee Dong; López-Berestein, Gabriel; Sood, Anil K.; Pan, Hui Lin

doi:10.1074/jbc.m112.395830

Cited by 131 publications

(168 citation statements)

References 63 publications

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“…2012; Zhou et al . 2012). Banke & Gegelashvili (2008) found that promoting PKC activity (with phorbol 12‐myristate 13‐acetate, a broad activator of protein kinase C) resulted in a hyperpolarizing shift in E GABA , and inhibition of PKC (using Gö6976) resulted in a depolarizing shift in E GABA .…”

Section: Gpcr Modulation: a Brief Overviewmentioning

confidence: 99%

Regulation of neuronal chloride homeostasis by neuromodulators

Mahadevan

Woodin

2016

The Journal of Physiology

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KCC2 is the central regulator of neuronal Cl− homeostasis, and is critical for enabling strong hyperpolarizing synaptic inhibition in the mature brain. KCC2 hypofunction results in decreased inhibition and increased network hyperexcitability that underlies numerous disease states including epilepsy, neuropathic pain and neuropsychiatric disorders. The current holy grail of KCC2 biology is to identify how we can rescue KCC2 hypofunction in order to restore physiological levels of synaptic inhibition and neuronal network activity. It is becoming increasingly clear that diverse cellular signals regulate KCC2 surface expression and function including neurotransmitters and neuromodulators. In the present review we explore the existing evidence that G‐protein‐coupled receptor (GPCR) signalling can regulate KCC2 activity in numerous regions of the nervous system including the hypothalamus, hippocampus and spinal cord. We present key evidence from the literature suggesting that GPCR signalling is a conserved mechanism for regulating chloride homeostasis. This evidence includes: (1) the activation of group 1 metabotropic glutamate receptors and metabotropic Zn2+ receptors strengthens GABAergic inhibition in CA3 pyramidal neurons through a regulation of KCC2; (2) activation of the 5‐hydroxytryptamine type 2A serotonin receptors upregulates KCC2 cell surface expression and function, restores endogenous inhibition in motoneurons, and reduces spasticity in rats; and (3) activation of A3A‐type adenosine receptors rescues KCC2 dysfunction and reverses allodynia in a model of neuropathic pain. We propose that GPCR‐signals are novel endogenous Cl− extrusion enhancers that may regulate KCC2 function.

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Section: Gpcr Modulation: a Brief Overviewmentioning

confidence: 99%

Regulation of neuronal chloride homeostasis by neuromodulators

Mahadevan

Woodin

2016

The Journal of Physiology

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“…The ultimate goal of any sickle cell therapy is the reduction of chronic pain and episodes of acute pain crises in patients with SCD [101]. In rat models of spinal nerve injury, inhibition of calpain-1 reduced neuropathic pain [102]. Thus, evaluated whether experimental sickle mice SSCKO would show a reduction in pain behaviors that have been previously characterized in the Berkeley and Townes sickle mice [99].…”

Section: Calpain 1 Therapymentioning

confidence: 99%

Non-Conventional Pain Management for Sickle Cell Disease

Al-Jafar¹

2017

Ann Hematol Oncol

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Sickle cell disease is a congenital blood disorder affecting hemoglobin molecule. It leads to a rigid, sickle like shape red blood cell. Most people with sickle cell disease have severe painful episodes called vaso-occlusive crises. However, the frequency, severity, and duration of these crises vary tremendously. The pain is classified into two types, nociception pain which is intact peripheral or central nervous system and neuropathic pain which is initiated by dysfunction of the peripheral or central nervous system. Despite the pain being the most common complication of sickle cell disease, there is a lack of novel pain treatments. Pain killers including opioid have continued to be the main stay of therapy over the past several decades. A non-conventional treatments for pain were applied effectively to avoid the serious systemic side effects of the pharmaceutical pain killers.

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“…We used CGP55845 to minimize the confounding effect of GABA B receptor activation (via G protein-coupled inwardly rectifying K ϩ channels) on the GABA reversal potential (E GABA ) and membrane potential during GABA application. The E GABA was determined by using linear regression to calculate a best fit line for the voltage dependence of chloride-mediated currents, and the intercept of the current-voltage line with the abscissa was taken as E GABA (17,25). In some experiments, the membrane voltage responses of lamina II neurons to GABA (100 M) puff application were measured and quantified.…”

Section: Methodsmentioning

confidence: 99%

“…For recording the membrane potential and GABA reversal potential (E GABA ), we used the Cl Ϫ -impermeable gramicidinperforated patch clamp method (17,25). The glass pipette solution contained 140 mM CsCl, 5 mM EGTA, and 10 mM HEPES, pH 7.4.…”

Section: Methodsmentioning

confidence: 99%

“…However, little is known about how paclitaxel affects spinal nociceptive processing or about its role in neuropathic pain. The cation-Cl Ϫ cotransporters, * This work was supported, in whole or in part, by National Institutes of Health NKCC1 and KCC2, play important roles in balancing intracellular Cl Ϫ concentrations in spinal dorsal horn neurons (16,17). GABA and glycine are critically involved in regulating nociceptive input in the spinal cord.…”

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confidence: 99%

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Increased Spinal Cord Na+-K+-2Cl− Cotransporter-1 (NKCC1) Activity Contributes to Impairment of Synaptic Inhibition in Paclitaxel-induced Neuropathic Pain

Chen

Zhu

Chen

et al. 2014

Journal of Biological Chemistry

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Background: Spinal synaptic plasticity may contribute to paclitaxel-induced painful neuropathy. Results: Paclitaxel treatment impairs GABA-mediated neuronal inhibition and increases total and plasma membrane NKCC1 protein levels in the spinal cord. Blocking NKCC1 reverses paclitaxel effects on synaptic inhibition and pain hypersensitivity. Conclusion: Paclitaxel diminishes synaptic inhibition in the spinal cord. Significance: This study demonstrates how disrupting microtubule dynamics causes synaptic plasticity and neuropathic pain.

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N-Methyl-d-aspartate Receptor- and Calpain-mediated Proteolytic Cleavage of K+-Cl− Cotransporter-2 Impairs Spinal Chloride Homeostasis in Neuropathic Pain

Cited by 131 publications

References 63 publications

Regulation of neuronal chloride homeostasis by neuromodulators

Regulation of neuronal chloride homeostasis by neuromodulators

Non-Conventional Pain Management for Sickle Cell Disease

Increased Spinal Cord Na+-K+-2Cl− Cotransporter-1 (NKCC1) Activity Contributes to Impairment of Synaptic Inhibition in Paclitaxel-induced Neuropathic Pain

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