KCa3.1 channels modulate the processing of noxious chemical stimuli in mice

Lu, Ruirui; Flauaus, Cathrin; Kennel, Lea; Petersen, Jonas; Drees, Oliver; Kallenborn-Gerhardt, Wiebke; Ruth, Peter; Łukowski, Robert; Schmidtko, Achim

doi:10.1016/j.neuropharm.2017.08.021

Cited by 27 publications

(30 citation statements)

References 74 publications

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“…Finally, recent evidence suggests that IK inhibitors should be used with caution since they may also increase tonic pain in certain clinical conditions. A recent study demonstrated that pharmacological inhibition of IK channels using TRAM-34 in mice increased formalin-induced nociceptive behavior ( Lu et al, 2017 ). Conversely, another study showed that blocking IK channels with Senicapoc reversed tactile allodynia in rats with peripheral nerve injury ( Staal et al, 2017 ).…”

Section: Regulation Of K Ca Channels and Implicatimentioning

confidence: 99%

Physiological Roles and Therapeutic Potential of Ca2+ Activated Potassium Channels in the Nervous System

Kshatri

Gonzalez-Hernandez

Giráldez

2018

Front. Mol. Neurosci.

106

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Within the potassium ion channel family, calcium activated potassium (KCa) channels are unique in their ability to couple intracellular Ca2+ signals to membrane potential variations. KCa channels are diversely distributed throughout the central nervous system and play fundamental roles ranging from regulating neuronal excitability to controlling neurotransmitter release. The physiological versatility of KCa channels is enhanced by alternative splicing and co-assembly with auxiliary subunits, leading to fundamental differences in distribution, subunit composition and pharmacological profiles. Thus, understanding specific KCa channels’ mechanisms in neuronal function is challenging. Based on their single channel conductance, KCa channels are divided into three subtypes: small (SK, 4–14 pS), intermediate (IK, 32–39 pS) and big potassium (BK, 200–300 pS) channels. This review describes the biophysical characteristics of these KCa channels, as well as their physiological roles and pathological implications. In addition, we also discuss the current pharmacological strategies and challenges to target KCa channels for the treatment of various neurological and psychiatric disorders.

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Section: Regulation Of K Ca Channels and Implicatimentioning

confidence: 99%

Physiological Roles and Therapeutic Potential of Ca2+ Activated Potassium Channels in the Nervous System

Kshatri

Gonzalez-Hernandez

Giráldez

2018

Front. Mol. Neurosci.

106

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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%

“…Thus, as NSC-34 cells continue to differentiate with RA, the resultant decrease in the amplitude of TRAM-34-sensitive I K due to the decreased activity of IK Ca channels may not only produce a progressive reduction of K + efflux and depolarize the cell but also may result in the suppression of after-hyperpolarizing potentials [11,14]. Such maintained membrane depolarization accompanied by an increase in neuronal excitability would be prepared to elicit voltage-gated Na + or Ca 2+ currents in response to depolarizing inputs, thereby inducing regenerative neuronal firing [13,26]. Thus, under cell-attached or inside-out recordings, a sustained decrease in IK Ca -channel activity during RA-induced differentiation may ultimately be related to neuronal differentiation or excitability in NSC-34 cells.…”

Section: Discussionmentioning

confidence: 99%

“…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%

“…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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The effects of a galectin‐3 inhibitor on bladder pain syndrome in mice with cyclophosphamide‐induced cystitis

Xiao,

Wang,

Gao

et al. 2024

Neurourology and Urodynamics

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AimsTo explore the effect of blocking galectin‐3 in the bladder pain syndrome associated with interstitial cystitis.MethodsA galectin‐3 inhibitor was used to treat mice with cyclophosphamide‐induced cystitis. The expression of galectin‐3 in bladder tissues and urine was examined by immunohistochemistry and enzyme‐linked immunosorbent assay (ELISA), respectively. Suprapubic‐pelvic pain, bladder voiding, bladder pain‐like nociceptive behavior, and referred hyperalgesia were assessed. The weights of the bladders were also measured, and inflammatory cell infiltration and inflammatory cytokine levels were examined by histopathological evaluation. The inflammatory cytokines interleukin 1β (IL‐1β), nerve growth factor (NGF), IL‐6, and tumor necrosis factor α (TNF‐α) were measured by ELISA.ResultsIncreases in galectin‐3 levels, inflammation, bladder weight, and bladder pain‐related symptoms were observed in bladders with cyclophosphamide‐induced cystitis. Administration of the galectin‐3 inhibitor significantly mitigated bladder pain‐related symptoms and inflammatory response. In response to the 500 μM dose of the galectin‐3 inhibitor, nociceptive behaviors, nociceptive score, and bladder‐to‐body weight ratios were reduced by 65.1%, 65.3%, and 40.3%, respectively, while 500 μM Gal‐3 inhibitor increased pelvic pain threshold by 86.7%. Moreover, galectin‐3 inhibitor treatment inhibited the inflammation. Compared to untreated CYP‐induced mice, there were significant changes in the levels of IL‐1β (41.72 ± 2.05 vs. 18.91 ± 2.26 pg/mg tissues), NGF (9.64 ± 0.38 vs. 1.88 ± 0.05 pg/mg tissues), IL‐6 (42.67 + 1.51 vs. 21.26 + 2.78 pg/mg tissues, and TNF‐α (22.02 ± 1.08 vs. 10.70 ± 0.80 pg/mg tissues) in response to the highest dose of the Gal‐3 inhibitor subgroup (500 μM), and 500 μM Gal‐3 inhibitor reduced mast cell infiltration ratios by 71.8%.ConclusionsThe galectin‐3 inhibitor relieved pelvic pain, urinary symptoms, and bladder inflammation in mice with cyclophosphamide‐induced cystitis. Thus, galectin‐3 inhibitors may be novel agents in interstitial cystitis treatment.

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KCa3.1 channels modulate the processing of noxious chemical stimuli in mice

Cited by 27 publications

References 74 publications

Physiological Roles and Therapeutic Potential of Ca2+ Activated Potassium Channels in the Nervous System

Physiological Roles and Therapeutic Potential of Ca2+ Activated Potassium Channels in the Nervous System

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

The effects of a galectin‐3 inhibitor on bladder pain syndrome in mice with cyclophosphamide‐induced cystitis

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