Inhibition of the Ca2+-Dependent K+Channel,KCNN4/KCa3.1, Improves Tissue Protection and Locomotor Recovery after Spinal Cord Injury

Bouhy, Delphine; Ghasemlou, Nader; Lively, Starlee; Redensek, Adriana; Rathore, Khizr I.; Schlichter, Lyanne C.; David, Samuel

doi:10.1523/jneurosci.0047-11.2011

Cited by 69 publications

(70 citation statements)

References 66 publications

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“…However, we could not observe any change in the expression level of BK channels in spinal microglia after PNI [16]. The immunoreactivity for SK channels was never detected in the spinal microglia even after cellular activation [35]. These findings corresponded well to our data that current activation in BK channels but not SK channels is a specific event in the activated spinal microglia.…”

Section: Molecular Target For Analgesic Effect Of Ketaminesupporting

confidence: 90%

BK channel in microglia as a potent therapeutic molecular target for neuropathic pain

Hayashi

Nakanishi

2015

Journal of Oral Biosciences

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a b s t r a c tBackground: Ketamine, noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, has been used in the treatment of chronic neuropathic pain. However, serious troubles have still remained in ketamine for the clinical treatment because of the strong adverse side effects during the long-term use. S-ketamine, one of the ketamine enantiomers, has a potent analgesic effect and weak side effects compared with R-ketamine. To date, analgesic potency of S-and R-ketamine was not been fully accounted for in the binding affinity to NMDA receptors. In the present review, we provide a novel analgesic mechanism of ketamine on chronic pain. Highlight: Spinal microglia after nerve injury activate Ca 2 þ -binding site of Ca 2 þ -activated K þ (BK) channels. S-ketamine significantly inhibited BK channel activation in spinal microglia. Intrathecal administration of BK channel activator mimics allodynia-like behavior, which was completely inhibited by S-ketamine. BK channel inhibitor alleviated neuropathic pain. BK channel inhibitor suppressed microglial activation in the spinal dorsal horn. Conclusion: These findings suggest that potent analgesic effects of S-ketamine arise from the inhibition of microglial BK channels, in addition to neuronal NMDA receptors. Thus, BK channels in microglia are a potential target for the treating of neuropathic pain.

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Section: Molecular Target For Analgesic Effect Of Ketaminesupporting

confidence: 90%

BK channel in microglia as a potent therapeutic molecular target for neuropathic pain

Hayashi

Nakanishi

2015

Journal of Oral Biosciences

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“…Thus, the magnitude of the K Ca 3.1 current may be influenced by the electrical behaviors of neurons. However, studies have shown that the activity of IK Ca channels can be enhanced under conditions where Ca 2+ channels are facilitated by neuronal activity [9,11,13,26]. Thus, notably, under culture conditions with no optimized stimulus, the activity of IK Ca channels inherent in neurons occurring in vitro accompanied by any associated biochemical changes or signaling transduction processes could, to some extent, have been underestimated in the present study.…”

Section: Discussionmentioning

confidence: 68%

“…Despite being in the same gene family as K Ca 2.x, K Ca 3.1 channels share only approximately 45% sequence homology [7]; in particular, these channels exhibit single-channel conductance of 20-60 pS, and their pharmacological profiles are considerably distinguishable from those of large-and small-conductance Ca 2+ -activated K + channels. However, the modulators of functional IK Ca channels have been demonstrated to perturb the functional activities of central neurons including motor neurons [8][9][10][11][12][13]. More specifically, the activity of these channels increases as voltage-gated Ca 2+ channels are facilitated by overactivity or neuron recovery (e.g., motor neuron recovery) during spinal cord injuries [8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

“…However, the modulators of functional IK Ca channels have been demonstrated to perturb the functional activities of central neurons including motor neurons [8][9][10][11][12][13]. More specifically, the activity of these channels increases as voltage-gated Ca 2+ channels are facilitated by overactivity or neuron recovery (e.g., motor neuron recovery) during spinal cord injuries [8][9][10][11]. K Ca 3.1 channels appear to be strongly linked to a phenotype of hyperactivity disorder, at least in mice [13].…”

Section: Introductionmentioning

confidence: 99%

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Evidence of Decreased Activity in Intermediate-Conductance Calcium-Activated Potassium Channels During Retinoic Acid–Induced Differentiation in Motor Neuron–Like NSC-34 Cells

Chen

Ruan

2018

Cell Physiol Biochem

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Background/Aims: Intermediate-conductance Ca²⁺-activated K⁺ (IK_Ca; K_Ca3.1 or KCNN4) channels affect the behaviors of central neurons including motor neurons. The mechanism through which neuronal differentiation is related to the activity of these channels remains largely unclear. Methods: By using various molecular biology tools and electrophysiological measurements, we investigated possible changes in the activity of IK_Ca channels in a retinoic acid (RA)-induced differentiation process in motor neuron-like NSC-34 cells. Results: The protein and messenger RNA expression of K_Ca3.1 substantially diminished as NSC-34 cells were differentiated with low serum (1%) and 1 µM RA. In whole-cell current recordings, the density of delayed-rectifier K⁺ currents obtained from differentiated cells was elevated. However, the density of a ramp pulse-elicited K⁺ current that was sensitive to blockage by 1-((2-chlorophenyl) (diphenyl)methyl)-1H-pyrazole (TRAM-34)—an inhibitor of IK_Ca channels—was significantly higher in undifferentiated NSC-34 cells than in differentiated cells. In undifferentiated cells, the activity of IK_Ca channels was readily detected and the probability of channel openings was resistant to stimulation by diazoxide or suppression by verruculogen. Furthermore, this probability was increased by 5,6-dichloro-1-ethyl-1,3-dihydro-2H-benzimidazol-2-one or 9-phenanthrol and reduced by TRAM-34. The channel-opening probability decreased in RA-induced differentiated cells, whereas the single-channel conductance of IK_Ca channels did not differ between undifferentiated and differentiated cells. Moreover, the slow component of the mean closed time in these channels was significantly shorter in undifferentiated cells than in differentiated cells; however, the mean open time in the channel remained unchanged as cells were differentiated. Conclusion: RA-induced differentiation in neurons could exert a suppressive effect on the activity of IK_Ca channels.

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“…TRAM34, synthesized by Wulff et al [137] in 2000, is currently the most widely used pharmacological tool compound for investigating the biology of K Ca 3.1 based on its high selectivity for K Ca 3.1 and its availability to academic researchers. To date, TRAM34 has been tested in various animal models, including ischaemia/reperfusion in stroke [138] and restenosis [83] in rats, traumatic spinal cord injury [139], atherosclerosis [30] and inflammatory bowel disease [140] in mice, and angioplasty in pigs [9].…”

Section: Pharmacological Blockers Of K Ca 31mentioning

confidence: 99%

Role of the potassium channel KCa3.1 in diabetic nephropathy

2014

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There is an urgent need to identify novel interventions for mitigating the progression of diabetic nephropathy. Diabetic nephropathy is characterized by progressive renal fibrosis, in which tubulointerstitial fibrosis has been shown to be the final common pathway of all forms of chronic progressive renal disease, including diabetic nephropathy. Therefore targeting the possible mechanisms that drive this process may provide novel therapeutics which allow the prevention and potentially retardation of the functional decline in diabetic nephropathy. Recently, the Ca2+-activated K+ channel KCa3.1 (KCa3.1) has been suggested as a potential therapeutic target for nephropathy, based on its ability to regulate Ca2+ entry into cells and modulate Ca2+-signalling processes. In the present review, we focus on the physiological role of KCa3.1 in those cells involved in the tubulointerstitial fibrosis, including proximal tubular cells, fibroblasts, inflammatory cells (T-cells and macrophages) and endothelial cells. Collectively these studies support further investigation into KCa3.1 as a therapeutic target in diabetic nephropathy.

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Inhibition of the Ca²⁺-Dependent K⁺Channel,KCNN4/KCa3.1, Improves Tissue Protection and Locomotor Recovery after Spinal Cord Injury

Abstract: Spinal cord injury (SCI) triggers inflammatory responses that involve neutrophils, macrophages/microglia and astrocytes and molecules

Cited by 69 publications

References 66 publications

BK channel in microglia as a potent therapeutic molecular target for neuropathic pain

BK channel in microglia as a potent therapeutic molecular target for neuropathic pain

Evidence of Decreased Activity in Intermediate-Conductance Calcium-Activated Potassium Channels During Retinoic Acid–Induced Differentiation in Motor Neuron–Like NSC-34 Cells

Role of the potassium channel KCa3.1 in diabetic nephropathy

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