Targeting Kv7 channels in pain pathways

Rivera-Arconada, Iván; Vicente-Baz, Jorge; López-García, J.A.

doi:10.18632/oncotarget.15261

Cited by 10 publications

(10 citation statements)

References 8 publications

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“…Our study also demonstrated that KCNQ was distributed in HPrSM. The Kv7 potassium channels, formerly known as the KCNQ family, are composed of five subunits from 1 to 5 14 . In real‐time PCR analyses, there were some differences between HPrSM cells and human prostate tissue with regard to the relative abundance of KCNQ subtypes.…”

Section: Discussionmentioning

confidence: 99%

“…The role of the new pharmacologic activator of Kv7 channels, ML213 (N‐(2,4,6‐trimethylphenyl)‐bicyclo[2.2.1]heptane‐2‐carboxamide, C17H23NO), is being reported in various areas such as vascular smooth muscle or pain pathways 14,15 . Besides, a comparison of the effect with retigabine, another Kv7.2–5 channel activator, has also been reported 16 …”

Section: Introductionmentioning

confidence: 99%

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Molecular expression and functional features of Kv7 channels in human prostate smooth muscle

et al. 2021

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Background Relaxation of prostate smooth muscle tone is a key strategy for the medical treatment of lower urinary tract symptoms (LUTS) in men. However, potassium channel's physiological role inhuman prostatic smooth muscle (HPrSM) has yet to be determined. Objectives In this study, we examined the molecular characteristics and physiological roles of Kv7 channels in HPrSM. Materials and methods The expressions of KCNQ1–5 (Kv7 channel pore‐forming α‐subunits) and KCNE1‐5 (β‐regulatory subunits) isoforms in HPrSM were examined using real‐time PCR. The relaxation effect of ML213 was investigated by cumulatively adding ML213 to the prostate strips. Kv7 currents were recorded using an amphotericin‐B perforated patch‐clamp technique. Results In HPrSM cells, KCNQ4, KCNQ5, and KCNE4 isoforms were predominantly expressed, while KCNQ1, KCNQ5, and KCNE3 isoforms were the most abundantly expressed in human prostatic tissues. Western blot analysis revealed the protein expression of the Kv7.1, 7.4, and 7.5 channel subtypes in human prostate tissues (n = 3). ML213 (an activator of Kv7.2/7.4/7.5) induced the concentration‐dependent relaxation of HPrSM strips (n = 15, p = 0.001), and this effect was attenuated by pretreatment with XE991 (a Kv7.1–7.5 blocker). In electrophysiology studies, ML213 significantly increased the amplitude of whole‐cell Kv7 currents in HPrSM cells. ML213‐induced outward currents were greater than retigabine (a Kv7.2–7.5 channel activator). The subsequent addition of XE991 completely inhibited the ML213‐induced currents (n = 9, p < 0.01 vs. ML213). ML213 hyperpolarized the HPrSM cell membrane potential and was fully reversed by XE991. In situ PLA revealed the colocalization of heteromeric KV7.4/KV7.5 channels in HPrSM cells. Conclusions Our findings suggest that Kv7.4 and 7.5 channels in prostatic smooth muscle play a critical role in the regulation of HPrSM tone and that Kv7 channel subtypes may be novel therapeutic targets for the treatment of LUTS associated with BPH.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Molecular expression and functional features of Kv7 channels in human prostate smooth muscle

et al. 2021

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“…K v 1.1/K v 1.2 are mainly found in large non-nociceptive neurons [ 220 ]. K v 7 channels, encoded by KCNQ1-5 historically named “M-channel” as it explained the observed non-inactivating potassium “M-current,” are a focus of pharmaceutical development since K v 7 activation has demonstrated analgesic potential for inflammatory and neuropathic pain [ 221 , 222 ]. Many of the respective studies used K v 7 blocker XE-991 or K v 7 activator retigabine [ 223 , 224 ].…”

Section: Effects Predominantly or Exclusively On Sensory Neuronsmentioning

confidence: 99%

Novel Analgesics with Peripheral Targets

Ciotu

Fischer

2020

Neurotherapeutics

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A limited number of peripheral targets generate pain. Inflammatory mediators can sensitize these. The review addresses targets acting exclusively or predominantly on sensory neurons, mediators involved in inflammation targeting sensory neurons, and mediators involved in a more general inflammatory process, of which an analgesic effect secondary to an anti-inflammatory effect can be expected. Different approaches to address these systems are discussed, including scavenging proinflammatory mediators, applying anti-inflammatory mediators, and inhibiting proinflammatory or facilitating anti-inflammatory receptors. New approaches are contrasted to established ones; the current stage of progress is mentioned, in particular considering whether there is data from a molecular and cellular level, from animals, or from human trials, including an early stage after a market release. An overview of publication activity is presented, considering a IuPhar/BPS-curated list of targets with restriction to pain-related publications, which was also used to identify topics.

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“…[ 2 3 4 ] These channels were formally called KCNQ channels. [ 5 ] These channels are voltage-gated, 6-transmembrane channels involved in controlling cell excitability. [ 4 ] Flupirtine, in addition to acting as a Kv7 channel opener in neurons, also opens Kv7 channels in other body tissues such as smooth muscles.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of spontaneous contractility of isolated caprine ureter by flupirtine

Naik

Kodagali

Tyagi

et al. 2018

Int J App Basic Med Res

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Context:Kv7 potassium channels are expressed in several types of smooth muscles and could mediate physiological responses in the tissues expressed. Flupirtine is an analgesic that acts by opening Kv7 potassium channels. It has been shown to inhibit the contractility of several types of isolated smooth muscle.Aims:This study investigated the ability of flupirtine to inhibit the spontaneous contractility of isolated distal caprine (goat) ureter.Settings and Design:Spontaneous contractility of the isolated goat ureter was recorded using a physiograph.Materials and Methods:The ability of 1, 3, 10, 30, and 90 μM concentrations of flupirtine maleate to inhibit the spontaneous contractility of isolated distal goat ureter was investigated. The ability of the nonspecific potassium channel blocker 4-aminopyridine (4-AP; 1 mM) and the specific Kv7 channel blocker XE-991 (100 μM) to reverse the inhibitory effect of flupirtine on ureteric contractility was also investigated.Statistical Analysis Used:Both parametric and nonparametric statistical tests were used.Results:At 10, 30, and 90 μM concentrations, flupirtine significantly inhibited the spontaneous contractility of the isolated goat ureter. The EC50 of flupirtine for a contact period of 10 min was 17.7 μM. The inhibitory effect of flupirtine on ureteric contractility was significantly reversed by 4-AP and XE-991.Conclusions:Flupirtine inhibits the spontaneous contractility of the isolated goat ureter by opening Kv7 channels.

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Targeting Kv7 channels in pain pathways

Cited by 10 publications

References 8 publications

Molecular expression and functional features of Kv7 channels in human prostate smooth muscle

Molecular expression and functional features of Kv7 channels in human prostate smooth muscle

Novel Analgesics with Peripheral Targets

Inhibition of spontaneous contractility of isolated caprine ureter by flupirtine

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