Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neuronal KCNQ (Kv7) channels (KCNQ2-5 or Kv7.2-7.5, disclosed to date) were discovered by virtue of their homology with a known cardiac channel involved in long QT syndrome (KvLQT or KCNQ1, Kv7.1) and first disclosed in 1998. The involvement of KCNQ2 (Kv7.2) and KCNQ3 (Kv7.3) in a benign idiopathic neonatal epilepsy, KCNQ4 (Kv7.4) in a form of congenital deafness, and the discovery that neuronal KCNQ heteromultimers were among the molecular substrates of M-channels, resulted in a high level of interest for potential drug development strategies. A number of small-molecule modulators were quickly identified, including openers or activators such as the antiepileptic drug candidate retigabine and the structurally-related analgesic drug flupirtine (Katadolon trade mark Asta Medica), and a group of KCNQ channel inhibitors/blockers originally developed for cognition enhancement. All of these data have suggested a rich target profile for modulators of neuronal KCNQ channels, including a variety of neuronal hyperexcitability disorders and conditions for openers, such as the epilepsies, acute pain, neuropathic pain, migraine pain and some neurodegenerative and psychiatric disorders. KCNQ blockers could likewise have utility in disorders characterised by neuronal hypoactivity, including cognition enhancement and perhaps disorders of mood. Emerging patent literature suggests significant interest in neuronal KCNQ modulation in the pharmaceutical industry and significant chemical diversity concerning KCNQ modulation.
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PMID:The therapeutic potential of neuronal KCNQ channel modulators. 1464 Sep 9

The family of Kv7 (KCNQ) potassium channels consists of five members. Kv7.2 and 3 are the primary molecular correlates of the M-current, but also Kv7.4 and Kv7.5 display M-current characteristics. M-channel modulators include blockers (e.g., linopirdine) for cognition enhancement and openers (e.g., retigabine) for treatment of epilepsy and neuropathic pain. We investigated the effect of a Bristol-Myers Squibb compound (S)-N-[1-(3-morpholin-4-yl-phenyl)-ethyl]-3-phenyl-acrylamide [(S)-1] on cloned human Kv7.1-5 potassium channels expressed in Xenopus laevis oocytes. Using two-electrode voltage-clamp recordings we found that (S)-1 blocks Kv7.1 and Kv7.1/KCNE1 currents. In contrast, (S)-1 produced a hyperpolarizing shift of the activation curve for Kv7.2, Kv7.2/Kv7.3, Kv7.4 and Kv7.5. Further, the compound enhanced the maximal current amplitude at all potentials for Kv7.4 and Kv7.5 whereas the combined activation/block of Kv7.2 and Kv7.2/3 was strongly voltage-dependent. The tryptophan residue 242 in S5, known to be crucial for the effect of retigabine, was also shown to be critical for the enhancing effect of (S)-1 and BMS204352. Furthermore, no additive effect on Kv7.4 current amplitude was observed when both retigabine and (S)-1 or BMS204352 were applied simultaneously. In conclusion, (S)-1 differentially affects the Kv7 channel subtypes and is dependent on a single tryptophan for the current enhancing effect in Kv7.4.
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PMID:The acrylamide (S)-1 differentially affects Kv7 (KCNQ) potassium channels. 1690 8

KCNQ genes encode five Kv7 K(+) channel subunits (Kv7.1-Kv7.5). Four of these (Kv7.2-Kv7.5) are expressed in the nervous system. Kv7.2 and Kv7.3 are the principal molecular components of the slow voltage-gated M-channel, which widely regulates neuronal excitability, although other subunits may contribute to M-like currents in some locations. M-channels are closed by receptors coupled to Gq such as M1 and M3 muscarinic receptors; this increases neuronal excitability and underlies some forms of cholinergic excitation. Muscarinic closure results from activation of phospholipase C and consequent hydrolysis and depletion of membrane phosphatidylinositol-4,5-bisphosphate, which is required for channel opening. Some effects of M-channel closure, determined from transmitter action, selective blocking drugs (linopirdine and XE991) and KCNQ2 gene disruption or manipulation, are as follows: (i) in sympathetic neurons: facilitation of repetitive discharges and conversion from phasic to tonic firing; (ii) in sensory nociceptive systems: facilitation of A-delta peripheral sensory fibre responses to noxious heat; and (iii) in hippocampal pyramidal neurons: facilitation of repetitive discharges, enhanced after-depolarization and burst-firing, and induction of spontaneous firing through a reduction of action potential threshold at the axon initial segment. Several drugs including flupirtine and retigabine enhance neural Kv7/M-channel activity, principally through a hyperpolarizing shift in their voltage gating. In consequence they reduce neural excitability and can inhibit nociceptive stimulation and transmission. Flupirtine is in use as a central analgesic; retigabine is under clinical trial as a broad-spectrum anticonvulsant and is an effective analgesic in animal models of chronic inflammatory and neuropathic pain.
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PMID:Neural KCNQ (Kv7) channels. 1929 56

Kv7.x channels are a family of six transmembrane domain, single pore-loop, voltage-gated K(+) channels. Five members of the family have been identified to date, including the cardiac channel Kv7.1 (formerly known as KvLQT1) and four neuronal Kv7.x channels, Kv7.2-5. Heteromeric channels containing Kv7.3 and either Kv7.2 or Kv7.5 are thought to underlie the neuronal M-current, a non-inactivating, slowly deactivating, sub-threshold current that has long been known to exert a powerful stabilizing influence on neuronal excitability. Modulators of these channels have the potential to influence neuronal activity in various tissues and are of much interest as therapeutic drug targets for the treatment of a variety of clinical disorders, such as epilepsy and pain. The purpose of the present article is to review the molecular, functional and behavioral evidence validating Kv7.x as drug targets for the treatment of pain. In addition, an update on pre-clinical Kv7 drug discovery efforts will be presented, along with a summary of on-going clinical trials with Kv7 channel activators.
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PMID:Kv7 channels as targets for the treatment of pain. 1944 90

Retigabine represents an antiepileptic drug possessing a completely different mechanism of action when compared to the existing classical and newer antiepileptic drugs. In the therapeutic range, retigabine enhances potassium currents, very likely via destabilization of a closed conformation or stabilization of the open conformation of the potassium Kv7.2-7.3 channels. There are also data indicating that this drug may be a GABA enhancer. Kainate-induced status epilepticus in rats resulted in massive apoptosis in the pyriform cortex and hippocampal area - retigabine inhibited neurodegeneration only in the former brain structure. The metabolism of retigabine has nothing to do with cytochrome P450 enzymes and the drug undergoes glucuronidation and acetylation. Randomized, placebo-controlled multicenter studies have shown that retigabine produced a considerable improvement as an add-on drug in patients with partial drug-resistant epilepsy. The most prominent adverse effects due to retigabine combined with the existing antiepileptic treatment were dizziness, somnolence and fatigue. The preclinical data indicate that this antiepileptic drug may possibly be applied in patients with neuropathic pain and affective disorders. Initial clinical data suggest that retigabine may be also effective in Alzheimer's disease or stroke.
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PMID:Retigabine: the newer potential antiepileptic drug. 2050 76

Regulation of the resting membrane potential and the repolarization of neurons are important in regulating neuronal excitability. The potassium channel subunits Kv7.2 and Kv7.3 play a key role in stabilizing neuronal activity. Mutations in KCNQ2 and KCNQ3, the genes encoding Kv7.2 and Kv7.3, cause a neonatal form of epilepsy, and activators of these channels have been identified as novel antiepileptics and analgesics. Despite the observations that regulation of these subunits has profound effects on neuronal function, almost nothing is known about the mechanisms responsible for controlling appropriate expression levels. Here we identify two mechanisms responsible for regulating KCNQ2 and KCNQ3 mRNA levels. We show that the transcription factor Sp1 activates expression of both KCNQ2 and KCNQ3, whereas the transcriptional repressor REST (repressor element 1-silencing transcription factor) represses expression of both of these genes. Furthermore, we show that transcriptional regulation of KCNQ genes is mirrored by the correlated changes in M-current density and excitability of native sensory neurons. We propose that these mechanisms are important in the control of excitability of neurons and may have implications in seizure activity and pain.
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PMID:Transcriptional control of KCNQ channel genes and the regulation of neuronal excitability. 2092 49

Neuropathic pain is a severe health problem for which there is a lack of effective therapy. A frequent underlying condition of neuropathic pain is a sustained overexcitability of pain-sensing (nociceptive) sensory fibres. Therefore, the identification of mechanisms for such abnormal neuronal excitability is of utmost importance for understanding neuropathic pain. Despite much effort, an inclusive model explaining peripheral overexcitability is missing. We investigated transcriptional regulation of the Kcnq2 gene, which encodes the Kv7.2 subunit of membrane potential-stabilizing M channel, in peripheral sensory neurons in a model of neuropathic pain-partial sciatic nerve ligation (PSNL). We show that Kcnq2 is the major Kcnq gene transcript in dorsal root ganglion (DRG); immunostaining and patch-clamp recordings from acute ganglionic slices verified functional expression of Kv7.2 in small-diameter nociceptive DRG neurons. Neuropathic injury induced substantial downregulation of Kv7.2 expression. Levels of repressor element 1-silencing transcription factor (REST), which is known to suppress Kcnq2 expression, were upregulated in response to neuropathic injury identifying the likely mechanism of Kcnq2 regulation. Behavioural experiments demonstrated that neuropathic hyperalgesia following PSNL developed faster than the downregulation of Kcnq2 expression could be detected, suggesting that this transcriptional mechanism may contribute to the maintenance rather than the initiation of neuropathic pain. Importantly, the decrease in the peripheral M channel abundance could be functionally compensated by peripherally applied M channel opener flupirtine, which alleviated neuropathic hyperalgesia. Our work suggests a novel mechanism for neuropathic overexcitability and brings focus on M channels and REST as peripheral targets for the treatment of neuropathic pain.
Pain 2011 Apr
PMID:Transcriptional repression of the M channel subunit Kv7.2 in chronic nerve injury. 2137 98

Kv7 (KCNQ) potassium channel openers (enhancers) decrease neuropathic pain in experimental models. Here we show that C-fibers, and their associated small-diameter neurons in the dorsal root ganglia (both IB4- and TrkA-positive), expressed Kv7.5. In contrast, C-fibers did not express detectable levels of Kv7.2 or Kv7.3, which are instead localized to nodes of Ranvier and the cell bodies of large sensory neurons. These data suggest that Kv7.5 provides the primary M current in nociceptive neurons.
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PMID:Kv7.5 is the primary Kv7 subunit expressed in C-fibers. 2213 95

M-type (Kv7, KCNQ) K(+) channels control the resting membrane potential of many neurons, including peripheral nociceptive sensory neurons. Several M channel enhancers were suggested as prospective analgesics, and targeting M channels specifically in peripheral nociceptors is a plausible strategy for peripheral analgesia. However, receptor-induced inhibition of M channels in nociceptors is often observed in inflammation and may contribute to inflammatory pain. Such inhibition is predominantly mediated by phospholipase C. We investigated four M channel enhancers (retigabine, flupirtine, zinc pyrithione and H(2)O(2)) for their ability to overcome M channel inhibition via two phospholipase C-mediated mechanisms, namely depletion of membrane phosphatidylinositol 4,5-bisphosphate (PIP(2)) and a rise in intracellular Ca(2+) (an action mediated by calmodulin). Data from overexpressed Kv7.2/Kv7.3 heteromers and native M currents in dorsal root ganglion neurons suggest the following conclusions. (i) All enhancers had a dual effect on M channel activity, a negative shift in voltage dependence and an increase of the maximal current at saturating voltages. The enhancers differed in their efficacy to produce these effects. (ii) Both PIP(2) depletion and Ca(2+)/calmodulin strongly reduced the M current amplitude; however, at voltages near the threshold for M channel activation (-60 mV) all enhancers were able to restore M channel activity to a control level or above, while at saturating voltages the effects were more variable. (iii) Receptor-mediated inhibition of M current in nociceptive dorsal root ganglion neurons did not reduce the efficacy of retigabine or flupirtine to hyperpolarize the resting membrane potential. In conclusion, we show that all four M channel enhancers tested could overcome both PIP(2) and Ca(2+)-calmodulin-induced inhibition of Kv7.2/7.3 at voltages close to the threshold for action potential firing (-60 mV) but generally had reduced efficacy at a saturating voltage (0 mV). We suggest that the efficacy of an M channel enhancer to shift the voltage dependence of activation may be most important for rescuing M channel function in sensory neurons innervating inflamed tissue.
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PMID:M channel enhancers and physiological M channel block. 2215 35

In ~30% of epileptic patients, full seizure control is not possible, which is why the search for novel antiepileptic drugs continues. Retigabine exhibits a mechanism of action that is not shared by the available antiepileptic drugs. This antiepileptic enhances potassium currents via Kv7.2-7.3 channels, which very likely results from destabilization of a closed conformation or stabilization of the open conformation of the channels. Generally, the pharmacokinetics of retigabine are linear and the drug undergoes glucuronidation and acetylation. Results from clinical trials indicate that, in the form of an add-on therapy, retigabine proves an effective drug in refractory epileptic patients. The major adverse effects of the add-on treatment are dizziness, somnolence, and fatigue. This epileptic drug is also considered for other conditions - neuropathic pain, affective disorders, stroke, or even Alzheimer's disease.
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PMID:Clinical utility of adjunctive retigabine in partial onset seizures in adults. 2229 49


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