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G C Rigdon - One of the best experts on this subject based on the ideXlab platform.
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N-(6-chloro-pyridin-3-yl)-3,4-difluoro-benzaMide (ICA-27243): a novel, selective KCNQ2/Q3 potassiuM channel activator
2016Co-Authors: Alan D Wickenden, J L Krajewski, Barry London, P K Wagoner, Wilkie A Wilson, Suzanne Clark, R Roeloffs, G. Mcnaughton-smith, G C RigdonAbstract:KCNQ2 (Kv7.2) and KCNQ3 (Kv7.3) are voltage-gated K chan-nel subunits that underlie the neuronal M Current. In huMans, Mutations in these genes lead to a rare forM of neonatal epi-lepsy (Biervert et al., 1998; Singh et al., 1998), suggesting that KCNQ2/Q3 channels May be attractive targets for novel anti-epileptic drugs. In the present study, we have identified the coMpound N-(6-chloro-pyridin-3-yl)-3,4-difluoro-benzaMide (ICA-27243) as a selective activator of the neuronal M Current and KCNQ2/Q3 channels. In SH-SY5Y huMan neuroblastoMa cells, ICA-27243 produced MeMbrane potential hyperpolar-ization that could be prevented by coadMinistration with the M-Current inhibitors 10,10-bis(4-pyridinylMethyl)-9(10H)-an-thracenone dihydrochloride (XE-991) and linopirdine. ICA-27243 enhanced both 86Rb efflux (EC50 0.2 M) an
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n 6 chloro pyridin 3 yl 3 4 difluoro benzaMide ica 27243 a novel selective kcnq2 q3 potassiuM channel activator
Molecular Pharmacology, 2008Co-Authors: Alan D Wickenden, J L Krajewski, Barry London, P K Wagoner, Wilkie A Wilson, Suzanne Clark, R Roeloffs, G Mcnaughtonsmith, G C RigdonAbstract:KCNQ2 (Kv7.2) and KCNQ3 (Kv7.3) are voltage-gated K(+) channel subunits that underlie the neuronal M Current. In huMans, Mutations in these genes lead to a rare forM of neonatal epilepsy (Biervert et al., 1998; Singh et al., 1998), suggesting that KCNQ2/Q3 channels May be attractive targets for novel antiepileptic drugs. In the present study, we have identified the coMpound N-(6-chloro-pyridin-3-yl)-3,4-difluoro-benzaMide (ICA-27243) as a selective activator of the neuronal M Current and KCNQ2/Q3 channels. In SH-SY5Y huMan neuroblastoMa cells, ICA-27243 produced MeMbrane potential hyperpolarization that could be prevented by coadMinistration with the M-Current inhibitors 10,10-bis(4-pyridinylMethyl)-9(10H)-anthracenone dihydrochloride (XE-991) and linopirdine. ICA-27243 enhanced both (86)Rb(+) efflux (EC(50) = 0.2 MicroM) and whole-cell Currents in Chinese haMster ovary cells stably expressing heteroMultiMeric KCNQ2/Q3 channels (EC(50) = 0.4 MicroM). Activation of KCNQ2/Q3 channels was associated with a hyperpolarizing shift of the voltage dependence of channel activation (V((1/2)) shift of -19 MV at 10 MicroM). In contrast, ICA-27243 was less effective at activating KCNQ4 and KCNQ3/Q5 and was selective over a wide range of neurotransMitter receptors and ion channels such as voltage-dependent sodiuM channels and GABA-gated chloride channels. ICA-27243 (1-10 MicroM) was found to reversibly suppress seizure-like activity in an ex vivo hippocaMpal slice Model of epilepsy and deMonstrated in vivo anticonvulsant activity (ED(50) = 8.4 Mg/kg) in the Mouse MaxiMal electroshock epilepsy Model. In conclusion, ICA-27243 represents the first MeMber of a novel cheMical class of selective KCNQ2/Q3 activators with anticonvulsant-like activity in experiMental Models of epilepsy.
Bertil Hille - One of the best experts on this subject based on the ideXlab platform.
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nerve growth factor sensitizes superior cervical ganglion neurons to bradykinin
Biophysical Journal, 2014Co-Authors: Oscar Vivas, Martin Kruse, Bertil HilleAbstract:The syMpathetic nervous systeM plays a role during chronic inflaMMation. Since levels of nerve growth factor (NGF) are high in inflaMed tissues and, in sensory neurons, NGF controls nociception by regulating neuronal sensitivity to noxious stiMuli, we hypothesize that NGF also sensitizes syMpathetic neurons to bradykinin (BK), a proinflaMMatory peptide. We cultured rat superior cervical ganglion (SCG) neurons in the presence or absence of NGF. To assess the response of SCG neurons to Bk, we Measured cytoplasMic Ca2+ elevations induced by an acute application of Bk. We found Ca2+ elevation to be increased 3-fold in the presence of NGF. These Ca2+ elevations in the presence of NGF depended on external Ca2+ and depolarization of the plasMa MeMbrane. Next, we assessed the effect of Bk on the MeMbrane potential by electrophysiological recordings. NGF-treated neurons were significantly depolarized after Bk application, while neurons cultured in the absence of NGF showed no change in MeMbrane potential with Bk. How does NGF render SCG neurons More responsive to a Bk stiMulus? We first tested whether NGF application alters BK-induced M Current inhibition. Interestingly, we observed full inhibition of M Current upon application of BK with and without culture in NGF. Next, we asked whether incubation of SCG neurons with NGF alters activity of other ion channels. One of the ion channels tested, KCa1.1 (Maxi K+ channel), was reduced in Current density by 50% in neurons cultured in the presence of NGF. In addition, inhibition of KCa1.1 channels with iberiotoxin in SCG neurons cultured in the absence of NGF depolarized the plasMa MeMbrane potential after Bk application. In conclusion, NGF increased Bk-induced electrical excitability of rat SCG neurons by reducing a repolarizing Current Mediated by KCa1.1 channels. Supported by NIH grant NS008174.
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fluorescence changes reveal kinetic steps of Muscarinic receptor Mediated Modulation of phosphoinositides and kv7 2 7 3 k channels
The Journal of General Physiology, 2009Co-Authors: Jill B Jensen, John S Lyssand, Chris Hague, Bertil HilleAbstract:G protein–coupled receptors initiate signaling cascades. M1 Muscarinic receptor (M1R) activation couples through Gαq to stiMulate phospholipase C (PLC), which cleaves phosphatidylinositol 4,5-bisphosphate (PIP2). Depletion of PIP2 closes PIP2-requiring Kv7.2/7.3 potassiuM channels (M Current), thereby increasing neuronal excitability. This Modulation of M Current is relatively slow (6.4 s to reach within 1/e of the steady-state value). To identify the rate-liMiting steps, we investigated the kinetics of each step using pairwise optical interactions likely to represent fluorescence resonance energy transfer for M1R activation, M1R/Gβ interaction, Gαq/Gβ separation, Gαq/PLC interaction, and PIP2 hydrolysis. Electrophysiology was used to Monitor channel closure. TiMe constants for M1R activation (<100 Ms) and M1R/Gβ interaction (200 Ms) are both fast, suggesting that neither of theM is rate liMiting during Muscarinic suppression of M Current. Gαq/Gβ separation and Gαq/PLC interaction have interMediate 1/e tiMes (2.9 and 1.7 s, respectively), and PIP2 hydrolysis (6.7 s) occurs on the tiMescale of M Current suppression. Overexpression of PLC accelerates the rate of M Current suppression threefold (to 2.0 s) to becoMe nearly conteMporaneous with Gαq/PLC interaction. Evidently, channel release of PIP2 and closure are rapid, and the availability of active PLC liMits the rate of M Current suppression.
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probing phosphoinositide kinetics with a voltage sensitive phosphatase
Biophysical Journal, 2009Co-Authors: Bjoern Falkenburger, Jill B Jensen, Byungchang Suh, Bertil HilleAbstract:Voltage-sensitive phosphatases (VSPs) have a voltage sensor linked to a phosphoinositide (PI) 5-phosphatase, which hydrolyzes plasMa MeMbrane PI-(4,5)-bisphosphate (PIP2) to PI(4)P (Iwasaki, PNAS 105, 7970). We used PIP2 hydrolysis by VSP froM Ciona intestinalis (ci-VSP) and zebrafish (dr-VSP) to better understand PIP2 binding and resynthesis. PIP2 was Monitored using the PIP2-sensitive M-Current (KCNQ2/3) and FRET between a pair of PIP2-binding probes (PH-PLCδ1-CFP & PH-PLCδ1-YFP). Depolarizations to +100 MV lasting >50 Ms reduced M-Current and PH-probe FRET. PIP2 depletion was saturated by depolarizations lasting 500-1000 Ms. Evidently PH-probe FRET and M-Current respond quickly to changes in plasMa MeMbrane PIP2.After repolarization, PH-probe FRET and M-Current relaxed to baseline values with tiMe constants of ~10 s in a wortMannin-insensitive Manner. This reflects endogenous PIP 5-kinase converting PI(4)P back to PI(4,5)P2. Overexpression of PIP 5-kinase increased the length of depolarization required to deplete PIP2, and speeded PIP2 recovery after repolarization.Recovery of PIP2 after VSP activation is ~10x faster than after PLC activation. However, it only requires PIP 5-kinase, whereas recovery after PLC activation requires PI 4-kinase and PIP 5-kinase in series. Thus PI 4-kinase Must be the slower enzyMe. To estiMate the rate of PI 4-kinase, we coMpared translocation of a fluorescent probe that reports plasMa MeMbrane PI(4)P (PH-OSH2, T.Balla) to translocation of the PIP2-binding probe in confocal tiMe-lapse iMaging. Upon PLC activation through M1 receptors, the plasMa MeMbrane PI(4)P signal decreased 20 s later than the PIP2 signal. Both probes recovered with siMilar tiMe courses. FRET photoMetry between either PIP2-probes or PI(4)P-probes showed coMparable results. The siMultaneous recovery of both probes is consistent with the hypothesis that recovery of PIP2 is governed by rate-liMiting synthesis of PI(4)P by the PI 4-kinase, followed by rapid conversion of PI(4)P into PI(4,5)P2 by the PIP 5-kinase.NIH-NS008174&HFSP
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gpr55 is a cannabinoid receptor that increases intracellular calciuM and inhibits M Current
Proceedings of the National Academy of Sciences of the United States of America, 2008Co-Authors: Jane E Lauckner, Huei Ying Chen, Huichen Lu, Jill B Jensen, Bertil Hille, Ken MackieAbstract:The CB1 cannabinoid receptor Mediates Many of the psychoactive effects of Δ9THC, the principal active coMponent of cannabis. However, aMple evidence suggests that additional non-CB1/CB2 receptors May contribute to the behavioral, vascular, and iMMunological actions of Δ9THC and endogenous cannabinoids. Here, we provide further evidence that GPR55, a G protein-coupled receptor, is a cannabinoid receptor. GPR55 is highly expressed in large dorsal root ganglion neurons and, upon activation by various cannabinoids (Δ9THC, the anandaMide analog MethanandaMide, and JWH015) increases intracellular calciuM in these neurons. ExaMination of its signaling pathway in HEK293 cells transiently expressing GPR55 found the calciuM increase to involve Gq, G12, RhoA, actin, phospholipase C, and calciuM release froM IP3R-gated stores. GPR55 activation also inhibits M Current. These results establish GPR55 as a cannabinoid receptor with signaling distinct froM CB1 and CB2.
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gpr55 is a cannabinoid receptor that increases intracellular calciuM and inhibits M Current
Proceedings of the National Academy of Sciences of the United States of America, 2008Co-Authors: Jane E Lauckner, Huei Ying Chen, Huichen Lu, Jill B Jensen, Bertil Hille, Ken MackieAbstract:The CB1 cannabinoid receptor Mediates Many of the psychoactive effects of Δ9THC, the principal active coMponent of cannabis. However, aMple evidence suggests that additional non-CB1/CB2 receptors May contribute to the behavioral, vascular, and iMMunological actions of Δ9THC and endogenous cannabinoids. Here, we provide further evidence that GPR55, a G protein-coupled receptor, is a cannabinoid receptor. GPR55 is highly expressed in large dorsal root ganglion neurons and, upon activation by various cannabinoids (Δ9THC, the anandaMide analog MethanandaMide, and JWH015) increases intracellular calciuM in these neurons. ExaMination of its signaling pathway in HEK293 cells transiently expressing GPR55 found the calciuM increase to involve Gq, G12, RhoA, actin, phospholipase C, and calciuM release froM IP3R-gated stores. GPR55 activation also inhibits M Current. These results establish GPR55 as a cannabinoid receptor with signaling distinct froM CB1 and CB2.
Kewei Wang - One of the best experts on this subject based on the ideXlab platform.
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activation of neuronal voltage gated potassiuM kv7 kcnq M Current by a novel channel opener scr2682 for alleviation of chronic pain
Journal of Pharmacology and Experimental Therapeutics, 2021Co-Authors: Jing Wang, Yani Liu, Jiuyong Yang, Xiaoyu Guo, Xingming Hou, Kewei WangAbstract:TreatMent of chronic pain reMains an unMet Medical need. The neuronal voltage-gated potassiuM Kv7/KCNQ/M channel has been iMplicated as a therapeutic target for chronic pain. However, whether pharMacological activation of the Kv7 channel can alleviate pain reMains elusive. In this study, we show that selective activation of native M-Currents by a novel channel opener SCR2682 reduces repetitive firings of dorsal root ganglia (DRG) sensory neurons. Intraperitoneal adMinistration of SCR2682 relieves Mechanical allodynia and therMal hyperalgesia in rat Models of pain induced by coMplete Freund's adjuvant (CFA) or spared nerve injury (SNI) in a dose-dependent Manner without affecting locoMotor activity. The antinociceptive efficacy of SCR2682 can be reversed by the channel-specific blocker XE991. FurtherMore, SCR2682 increases Kv7.2/KCNQ2 MRNA and protein expression in DRG neurons froM rats in the SNI Model of neuropathic pain. Taken together, pharMacological activation of neuronal Kv7 channels by opener SCR2682 can alleviate pain in rats, thus possessing therapeutic potential for chronic pain or hyperexcitability-related neurologic disorders. SIGNIFICANCE STATEMENT: A novel voltage-gated potassiuM Kv7 channel opener SCR2682 inhibits action potential firings in dorsal root ganglia sensory neurons and exhibits efficacy in antinociception, thus possessing a developMental potential for treatMent of chronic pain or epilepsy.
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activation of voltage gated kcnq kv7 channels by anticonvulsant retigabine attenuates Mechanical allodynia of inflaMMatory teMporoMandibular joint in rats
Molecular Pain, 2010Co-Authors: Wen Xu, Yeping Bi, Yuwei Wu, Kewei WangAbstract:Background: TeMporoMandibular disorders (TMDs) are characterized by persistent orofacial pain and have diverse etiologic factors that are not well understood. It is thought that central sensitization leads to neuronal hyperexcitability and contributes to hyperalgesia and spontaneous pain. Nonsteroidal anti-inflaMMatory drugs (NSAIDs) are Currently the first choice of drug to relieve TMD pain. NSAIDS were shown to exhibit anticonvulsant properties and suppress cortical neuron activities by enhancing neuronal voltage-gated potassiuM KCNQ/Kv7 channels (M-Current), suggesting that specific activation of M-Current Might be beneficial for TMD pain. Results: In this study, we selected a new anticonvulsant drug retigabine that specifically activates M-Current, and investigated the effect of retigabine on inflaMMation of the teMporoMandibular joint (TMJ) induced by coMplete Freund’s adjuvant (CFA) in rats. The results show that the head withdrawal threshold for escape froM Mechanical stiMulation applied to facial skin over the TMJ in inflaMed rats was significantly lower than that in control rats. AdMinistration of centrally acting M-channel opener retigabine (2.5 and 7.5 Mg/kg) can dose-dependently raise the head withdrawal threshold of Mechanical allodynia, and this analgesic effect can be reversed by the specific KCNQ channel blocker XE991 (3 Mg/kg). Food intake is known to be negatively associated with TMJ inflaMMation. Food intake was increased significantly by the adMinistration of retigabine (2.5 and 7.5 Mg/kg), and this effect was reversed by XE991 (3 Mg/kg). FurtherMore, intracerebralventricular injection of retigabine further confirMed the analgesic effect of central retigabine on inflaMMatory TMJ. Conclusions: Our findings indicate that central sensitization is involved in inflaMMatory TMJ pain and pharMacological intervention for controlling central hyperexcitability by activation of neuronal KCNQ/M-channels May have therapeutic potential for TMDs.
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activation of voltage gated kcnq kv7 channels by anticonvulsant retigabine attenuates Mechanical allodynia of inflaMMatory teMporoMandibular joint in rats
Molecular Pain, 2010Co-Authors: Lei Tan, Yehua Gan, Kewei WangAbstract:TeMporoMandibular disorders (TMDs) are characterized by persistent orofacial pain and have diverse etiologic factors that are not well understood. It is thought that central sensitization leads to neuronal hyperexcitability and contributes to hyperalgesia and spontaneous pain. Nonsteroidal anti-inflaMMatory drugs (NSAIDs) are Currently the first choice of drug to relieve TMD pain. NSAIDS were shown to exhibit anticonvulsant properties and suppress cortical neuron activities by enhancing neuronal voltage-gated potassiuM KCNQ/Kv7 channels (M-Current), suggesting that specific activation of M-Current Might be beneficial for TMD pain. In this study, we selected a new anticonvulsant drug retigabine that specifically activates M-Current, and investigated the effect of retigabine on inflaMMation of the teMporoMandibular joint (TMJ) induced by coMplete Freund's adjuvant (CFA) in rats. The results show that the head withdrawal threshold for escape froM Mechanical stiMulation applied to facial skin over the TMJ in inflaMed rats was significantly lower than that in control rats. AdMinistration of centrally acting M-channel opener retigabine (2.5 and 7.5 Mg/kg) can dose-dependently raise the head withdrawal threshold of Mechanical allodynia, and this analgesic effect can be reversed by the specific KCNQ channel blocker XE991 (3 Mg/kg). Food intake is known to be negatively associated with TMJ inflaMMation. Food intake was increased significantly by the adMinistration of retigabine (2.5 and 7.5 Mg/kg), and this effect was reversed by XE991 (3 Mg/kg). FurtherMore, intracerebralventricular injection of retigabine further confirMed the analgesic effect of central retigabine on inflaMMatory TMJ. Our findings indicate that central sensitization is involved in inflaMMatory TMJ pain and pharMacological intervention for controlling central hyperexcitability by activation of neuronal KCNQ/M-channels May have therapeutic potential for TMDs.
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validation of an atoMic absorption rubidiuM ion efflux assay for kcnq M channels using the ion channel reader 8000
Assay and Drug Development Technologies, 2004Co-Authors: Kewei Wang, Beal Mcilvain, Eugene Tseng, Dianne Kowal, Flora Jow, Ru Shen, Howard Zhang, Qin Jennifer Shan, Diana Chen, John DunlopAbstract:M-channels (M-Current), encoded by KCNQ2/3 K(+) channel genes, have eMerged as novel drug targets for a nuMber of neurological disorders. The lack of direct high throughput assays coMbined with the low throughput of conventional electrophysiology (EP) has iMpeded rapid screening and evaluation of K(+)-channel Modulators. DevelopMent of a sensitive and efficient assay for the direct MeasureMent of M-Current activity is critical for identifying novel M-channel Modulators and subsequent investigation of their therapeutic potential. Using a stable CHO cell line expressing rat KCNQ2/3 K(+) channels confirMed by EP, we have developed and validated a nonradioactive rubidiuM (Rb(+)) efflux assay in a 96-well plate forMat. The Rb(+) efflux assay directly Measures the activity of functional channels by atoMic absorption spectroscopy using the autoMated Ion Channel Reader (ICR) 8000. The stiMulated Rb(+) efflux froM KCNQ2/3-expressing cells was blocked by the channel blockers XE991 and linopirdine with IC(50) values of 0.15 MicroM and 1.3 MicroM, respectively. Twelve coMpounds identified as KCNQ2/3 openers were further assessed in this assay, and their EC(50) values were coMpared with those obtained with EP. A higher positive correlation coefficient between these two assays (r = 0.60) was observed than that between FlexStation MeMbrane potential and EP assays (r = 0.23). To siMplify the assay and increase the throughput, we deMonstrate that EC(50) values obtained by Measuring Rb(+) levels in the supernatant are as robust and consistent as those obtained froM the ratio of Rb(+) in supernatant/lysate. By Measuring the supernatant only, the throughput of ICR8000 in an eight-point titration is estiMated to be 40 coMpounds per day, which is suitable for a secondary confirMation assay.
Alan D Wickenden - One of the best experts on this subject based on the ideXlab platform.
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N-(6-chloro-pyridin-3-yl)-3,4-difluoro-benzaMide (ICA-27243): a novel, selective KCNQ2/Q3 potassiuM channel activator
2016Co-Authors: Alan D Wickenden, J L Krajewski, Barry London, P K Wagoner, Wilkie A Wilson, Suzanne Clark, R Roeloffs, G. Mcnaughton-smith, G C RigdonAbstract:KCNQ2 (Kv7.2) and KCNQ3 (Kv7.3) are voltage-gated K chan-nel subunits that underlie the neuronal M Current. In huMans, Mutations in these genes lead to a rare forM of neonatal epi-lepsy (Biervert et al., 1998; Singh et al., 1998), suggesting that KCNQ2/Q3 channels May be attractive targets for novel anti-epileptic drugs. In the present study, we have identified the coMpound N-(6-chloro-pyridin-3-yl)-3,4-difluoro-benzaMide (ICA-27243) as a selective activator of the neuronal M Current and KCNQ2/Q3 channels. In SH-SY5Y huMan neuroblastoMa cells, ICA-27243 produced MeMbrane potential hyperpolar-ization that could be prevented by coadMinistration with the M-Current inhibitors 10,10-bis(4-pyridinylMethyl)-9(10H)-an-thracenone dihydrochloride (XE-991) and linopirdine. ICA-27243 enhanced both 86Rb efflux (EC50 0.2 M) an
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n 6 chloro pyridin 3 yl 3 4 difluoro benzaMide ica 27243 a novel selective kcnq2 q3 potassiuM channel activator
Molecular Pharmacology, 2008Co-Authors: Alan D Wickenden, J L Krajewski, Barry London, P K Wagoner, Wilkie A Wilson, Suzanne Clark, R Roeloffs, G Mcnaughtonsmith, G C RigdonAbstract:KCNQ2 (Kv7.2) and KCNQ3 (Kv7.3) are voltage-gated K(+) channel subunits that underlie the neuronal M Current. In huMans, Mutations in these genes lead to a rare forM of neonatal epilepsy (Biervert et al., 1998; Singh et al., 1998), suggesting that KCNQ2/Q3 channels May be attractive targets for novel antiepileptic drugs. In the present study, we have identified the coMpound N-(6-chloro-pyridin-3-yl)-3,4-difluoro-benzaMide (ICA-27243) as a selective activator of the neuronal M Current and KCNQ2/Q3 channels. In SH-SY5Y huMan neuroblastoMa cells, ICA-27243 produced MeMbrane potential hyperpolarization that could be prevented by coadMinistration with the M-Current inhibitors 10,10-bis(4-pyridinylMethyl)-9(10H)-anthracenone dihydrochloride (XE-991) and linopirdine. ICA-27243 enhanced both (86)Rb(+) efflux (EC(50) = 0.2 MicroM) and whole-cell Currents in Chinese haMster ovary cells stably expressing heteroMultiMeric KCNQ2/Q3 channels (EC(50) = 0.4 MicroM). Activation of KCNQ2/Q3 channels was associated with a hyperpolarizing shift of the voltage dependence of channel activation (V((1/2)) shift of -19 MV at 10 MicroM). In contrast, ICA-27243 was less effective at activating KCNQ4 and KCNQ3/Q5 and was selective over a wide range of neurotransMitter receptors and ion channels such as voltage-dependent sodiuM channels and GABA-gated chloride channels. ICA-27243 (1-10 MicroM) was found to reversibly suppress seizure-like activity in an ex vivo hippocaMpal slice Model of epilepsy and deMonstrated in vivo anticonvulsant activity (ED(50) = 8.4 Mg/kg) in the Mouse MaxiMal electroshock epilepsy Model. In conclusion, ICA-27243 represents the first MeMber of a novel cheMical class of selective KCNQ2/Q3 activators with anticonvulsant-like activity in experiMental Models of epilepsy.
Johan F. Storm - One of the best experts on this subject based on the ideXlab platform.
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dorsoventral differences in kv7 M Current and its iMpact on resonance teMporal suMMation and excitability in rat hippocaMpal pyraMidal cells
The Journal of Physiology, 2015Co-Authors: Christoph Honigsperger, Mate Marosi, Ricardo Murphy, Johan F. StormAbstract:Key points Kv7 (KCNQ/M) channels are known to control excitability and generate subthreshold M-resonance in CA1 hippocaMpal pyraMidal cells, but their properties and functions have not previously been coMpared along the dorsoventral (septoteMporal) axis We used whole-cell recordings to coMpare electrophysiological properties of dorsal and ventral CA1 pyraMidal cells in hippocaMpal slices froM 3- to 4-week-old rats Blockade of Kv7/M-channels with 10,10-bis(4-pyridinylMethyl)-9(10H)-anthracenone dihydrochloride (XE991) had a stronger iMpact on electrical properties in dorsal than ventral pyraMidal cells, including input resistance, teMporal suMMation, M-resonance, spike threshold, MediuM after-hyperpolarization, excitability, and spike frequency adaptation. Voltage-claMp recordings revealed a larger aMplitude and left-shifted voltage dependence of XE991-sensitive Current (IM) in dorsal vs. ventral cells. IM-dependent differences in excitability and resonance May be iMportant for rate and phase coding of CA1 place cells along the dorsoventral axis and May enhance epileptiforM activity in ventral pyraMidal cells. Abstract In rodent hippocaMpi, the connections, gene expression and functions differ along the dorsoventral (D–V) axis. CA1 pyraMidal cells show increasing excitability along the D–V axis, although the underlying MechanisM is not known. In the present study, we investigated how the M-Current (IM), caused by Kv7/M (KCNQ) potassiuM channels, and known to often control neuronal excitability, contributes to D–V differences in intrinsic properties of CA1 pyraMidal cells. Using whole-cell patch claMp recordings and the selective Kv7/M blocker 10,10-bis(4-pyridinylMethyl)-9(10H)-anthracenone dihydrochloride (XE991) in hippocaMpal slices froM 3- to 4-week-old rats, we found that: (i) IM had a stronger iMpact on subthreshold electrical properties in dorsal than ventral CA1 pyraMidal cells, including input resistance, teMporal suMMation of artificial synaptic potentials, and M-resonance; (ii) IM activated at More negative potentials (left-shifted) and had larger peak aMplitude in the dorsal than ventral CA1; and (iii) the initial spike threshold (during raMp depolarizations) was elevated, and the MediuM after-hyperpolarization and spike frequency adaptation were increased (i.e. excitability was lower) in the dorsal rather than ventral CA1. These differences were abolished or reduced by application of XE991, indicating that they were caused by IM. Thus, it appears that IM has stronger effects in dorsal than in ventral rat CA1 pyraMidal cells because of a larger MaxiMal M-conductance and left-shifted activation curve in the dorsal cells. These MechanisMs May contribute to D–V differences in the rate and phase coding of position by CA1 place cells, and May also enhance epileptiforM activity in ventral CA1.
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expression and functional roles of kv7 kcnq M channels in rat Medial entorhinal cortex layer ii stellate cells
The Journal of Neuroscience, 2014Co-Authors: Maximiliano Jose Nigro, Pedro Mateosaparicio, Johan F. StormAbstract:The Medial entorhinal cortex (MEC) is iMportant for spatial navigation and MeMory. Stellate cells (SCs) of MEC layer II provide Major input to the hippocaMpus, and are thought to be the neuronal correlate of the grid cells. Their electrophysiological properties have been used to explain grid field forMation. However, little is known about the functional roles of potassiuM channels in SCs. M-Current is a slowly activating potassiuM Current, active at subthreshold potentials. Although soMe studies have suggested that Kv7/M-channels May affect subthreshold resonance in SCs, others have found no Kv7/M-Current in these cells, so the expression and roles of Kv7/M-channels in SCs are still debated. Using whole-cell voltage-claMp, we have identified a typical M-Current with pharMacological properties characteristic of Kv7/M-channels in rat MEC SCs. Current-claMp experiMents showed that the specific Kv7/M-channel blocker XE991 increased SCs excitability, and reduced spike frequency adaptation. Our results deMonstrate that Kv7/M-channels are expressed in SCs and contribute substantially to regulation of excitability in these cells.
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conditional transgenic suppression of M channels in Mouse brain reveals functions in neuronal excitability resonance and behavior
Nature Neuroscience, 2005Co-Authors: Christian H Peters, Olaf Pongs, Johan F. Storm, Hua Hu, Dirk IsbrandtAbstract:In huMans, Mutations in the KCNQ2 or KCNQ3 potassiuM-channel genes are associated with an inherited epilepsy syndroMe. We have studied the contribution of KCNQ/M-channels to the control of neuronal excitability by using transgenic Mice that conditionally express doMinant-negative KCNQ2 subunits in brain. We show that suppression of the neuronal M Current in Mice is associated with spontaneous seizures, behavioral hyperactivity and Morphological changes in the hippocaMpus. Restriction of transgene expression to defined developMental periods revealed that M-channel activity is critical to the developMent of norMal hippocaMpal Morphology during the first postnatal weeks. Suppression of the M Current after this critical period resulted in Mice with signs of increased neuronal excitability and deficits in hippocaMpus-dependent spatial MeMory. M-Current-deficient hippocaMpal CA1 pyraMidal neurons showed increased excitability, reduced spike-frequency adaptation, attenuated MediuM afterhyperpolarization and reduced intrinsic subthreshold theta resonance. M channels are thus critical deterMinants of cellular and neuronal network excitability, postnatal brain developMent and cognitive perforMance.
