The novel anticonvulsant retigabine activates M-currents in Chinese hamster ovary-cells tranfected with human KCNQ2/3 subunits

Rundfeldt, Chris; Netzer, Rainer

doi:10.1016/s0304-3940(00)00866-1

Cited by 232 publications

(169 citation statements)

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“…Direct activation of I M by retigabine has antiepileptic effects in vivo and in vitro Qiu et al, 2007;Rundfeldt, 1997;Rundfeldt and Netzer, 2000), and this drug is now in Phase III clinical trials for treating partial seizures (Porter et al, 2007). I M has a critical role in preventing the generation of seizures in hippocampus.…”

Section: Sst Inhibition Of Epileptiform Activity In Hippocampal Slicesmentioning

confidence: 99%

Somatostatin: An endogenous antiepileptic

Tallent

Qiu

2008

Molecular and Cellular Endocrinology

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The neuropeptide somatostatin is highly expressed in brain regions associated with seizures. In hippocampus, SST expression and release is regulated by seizures, and SST-containing neurons within the hilus of the dentate gyrus are sensitive to seizure-induced death. In vivo and in vitro studies suggest that the loss of SST function in the dentate could contribute to epileptogenesis and seizure susceptibility. SST also has inhibitory actions in the CA1 and CA3 hippocampus, indicating this peptide is an important homeostatic regulator throughout the hippocampus. In vivo studies show SST has robust antiepileptic properties, with the major site of action being hippocampus. In rodents, somatostatin receptor subtype 2 (SST 2 ) and SST 4 appear to mediate the majority of the antiepileptic actions of SST, with SST 2 predominate in rat and SST 4 in mouse. Thus SST receptors may be appropriate targets for new antiepileptic drugs, although validation in human tissue is lacking.

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Section: Sst Inhibition Of Epileptiform Activity In Hippocampal Slicesmentioning

confidence: 99%

Somatostatin: An endogenous antiepileptic

Tallent

Qiu

2008

Molecular and Cellular Endocrinology

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“…Activation of G q/11 -coupled receptors suppresses the Mcurrent, creating a slow excitatory postsynaptic potential, enhancing excitability and reducing spike-frequency adaptation 1,2 . The M-type K + channel is a promising therapeutic target, as the channel blocker linopirdine acts as a cognition enhancer 3,4 , and the channel activator retigabine functions as an anticonvulsant 5,6 . M-type channels are heteromeric complexes of certain KCNQ-family potassium channel subunits (KCNQ2-5) [7][8][9][10] .…”

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confidence: 99%

AKAP150 signaling complex promotes suppression of the M-current by muscarinic agonists

et al. 2003

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M-type (KCNQ2/3) potassium channels are suppressed by activation of G q/11 -coupled receptors, thereby increasing neuronal excitability. We show here that rat KCNQ2 can bind directly to the multivalent A-kinase-anchoring protein AKAP150. Peptides that block AKAP150 binding to the KCNQ2 channel complex antagonize the muscarinic inhibition of the currents. A mutant form of AKAP150, AKAP(ΔA), which is unable to bind protein kinase C (PKC), also attenuates the agonist-induced current suppression. Analysis of recombinant KCNQ2 channels suggests that targeting of PKC through association with AKAP150 is important for the inhibition. Phosphorylation of KCNQ2 channels was increased by muscarinic stimulation; this was prevented either by coexpression with AKAP(ΔA) or pretreatment with PKC inhibitors that compete with diacylglycerol. These inhibitors also reduced muscarinic inhibition of M-current. Our data indicate that AKAP150-bound PKC participates in receptor-induced inhibition of the M-current.The M-current is a low-threshold, slowly activating potassium current that exerts negative control over neuronal excitability. Activation of G q/11 -coupled receptors suppresses the Mcurrent, creating a slow excitatory postsynaptic potential, enhancing excitability and reducing spike-frequency adaptation 1,2 . The M-type K + channel is a promising therapeutic target, as the channel blocker linopirdine acts as a cognition enhancer 3,4 , and the channel activator retigabine functions as an anticonvulsant 5,6 . M-type channels are heteromeric complexes of certain KCNQ-family potassium channel subunits (KCNQ2-5) [7][8][9][10] . KCNQ2 and KCNQ3 were the first members of this family identified as M-channel forming subunits 7 . The KCNQ3 subunit is a core component that co-assembles with KCNQ2, KCNQ4 and KCNQ5 to form functional M-type channels 10 . © 2003 Nature Publishing GroupCorrespondence should be addressed to N.H. (hoshin@ohsu.edu). Note: Supplementary information is available on the Nature Neuroscience website. COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. NIH Public Access Author ManuscriptNat Neurosci. Author manuscript; available in PMC 2014 March 04. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptAlthough the subunits that form M-type K + channels have been identified, the molecular details of the signaling pathways that lead to suppression of the M-currents upon receptor stimulation have not yet been fully defined 2,11 . We know that inhibition results from activation of G proteins of the G q/11 family, with the α-subunit as the active moiety 12,13 , and that a 'diffusible' messenger is involved. That is, the receptor/G protein complex can be physically remote from the channel 14,15 . Thus, closure most likely results from some product of phospholipase C activity. M-type channels can be closed by raising intracellular calcium 16 , and there is evidence that this might be a 'second messenger' for bradykinin 17 and nucleotides 18 , but not...

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“…Individuals affected by BFNC typically display normal psychomotor development, although a higher incidence of various epileptic manifestations later in life has been reported (Ronen et al, 1993). In addition to its pathophysiological role in BFNC, I KM is emerging as a novel therapeutic target for CNS diseases; in fact, I KM activators such as retigabine and flupirtine (Main et al, 2000;Rundfeldt and Netzer, 2000;Wickenden et al, 2000;Martire et al, 2004) appear as promising therapeutic tools against epilepsy (Rostock et al, 1996), pain (Blackburn-Munro and Jensen, 2003; Passmore et al, 2003), anxiety (Korsgaard et al, 2005), dystonia (Richter et al, 2006), and neurodegenerative disorders (Otto et al, 2004;Boscia et al, 2006).…”

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confidence: 99%

Atypical Gating Of M-Type Potassium Channels Conferred by Mutations in Uncharged Residues in the S₄Region of KCNQ2 Causing Benign Familial Neonatal Convulsions

Soldovieri¹,

Cilio²,

Miceli³

et al. 2007

J. Neurosci.

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Heteromeric assembly of KCNQ2 and KCNQ3 subunits underlie the M-current (I KM ), a slowly activating and noninactivating neuronal K ϩ current. Mutations in KCNQ2 and KCNQ3 genes cause benign familial neonatal convulsions (BFNCs), a rare autosomal-dominant epilepsy of the newborn. In the present study, we describe the identification of a novel KCNQ2 heterozygous mutation (c587t) in a BFNC-affected family, leading to an alanine to valine substitution at amino acid position 196 located at the N-terminal end of the voltage-sensing S 4 domain. The consequences on KCNQ2 subunit function prompted by the A196V substitution, as well as by the A196V/L197P mutation previously described in another BFNC-affected family, were investigated by macroscopic and single-channel current measurements in CHO cells transiently transfected with wild-type and mutant subunits. When compared with KCNQ2 channels, homomeric KCNQ2 A196V or A196V/L197P channels showed a 20 mV rightward shift in their activation voltage dependence, with no concomitant change in maximal open probability or single-channel conductance. Furthermore, current activation kinetics of KCNQ2 A196V channels displayed an unusual dependence on the conditioning prepulse voltage, being markedly slower when preceded by prepulses to more depolarized potentials. Heteromeric channels formed by KCNQ2 A196V and KCNQ3 subunits displayed gating changes similar to those of KCNQ2 A196V homomeric channels. Collectively, these results reveal a novel role for noncharged residues in the N-terminal end of S 4 in controlling gating of I KM and suggest that gating changes caused by mutations at these residues may decrease I KM function, thus causing neuronal hyperexcitability, ultimately leading to neonatal convulsions.

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The novel anticonvulsant retigabine activates M-currents in Chinese hamster ovary-cells tranfected with human KCNQ2/3 subunits

Cited by 232 publications

References 15 publications

Somatostatin: An endogenous antiepileptic

Somatostatin: An endogenous antiepileptic

AKAP150 signaling complex promotes suppression of the M-current by muscarinic agonists

Atypical Gating Of M-Type Potassium Channels Conferred by Mutations in Uncharged Residues in the S₄Region of KCNQ2 Causing Benign Familial Neonatal Convulsions

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The novel anticonvulsant retigabine activates M-currents in Chinese hamster ovary-cells tranfected with human KCNQ2/3 subunits

Cited by 232 publications

References 15 publications

Somatostatin: An endogenous antiepileptic

Somatostatin: An endogenous antiepileptic

AKAP150 signaling complex promotes suppression of the M-current by muscarinic agonists

Atypical Gating Of M-Type Potassium Channels Conferred by Mutations in Uncharged Residues in the S4Region of KCNQ2 Causing Benign Familial Neonatal Convulsions

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Atypical Gating Of M-Type Potassium Channels Conferred by Mutations in Uncharged Residues in the S₄Region of KCNQ2 Causing Benign Familial Neonatal Convulsions