Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Discovery of a small molecule modulator of the Kv1.1/Kvβ1 channel complex that reduces neuronal excitability and in vitro epileptiform activity.
Niespodziany I
,
Mullier B
,
André VM
,
Ghisdal P
,
Jnoff E
,
Moreno-Delgado D
,
Swinnen D
,
Sands Z
,
Wood M
,
Wolff C
.
???displayArticle.abstract???
AIMS: Kv1.1 (KCNA1) channels contribute to the control of neuronal excitability and have been associated with epilepsy. Kv1.1 channels can associate with the cytoplasmic Kvβ1 subunit resulting in rapid inactivating A-type currents. We hypothesized that removal of channel inactivation, by modulating Kv1.1/Kvβ1 interaction with a small molecule, would lead to decreased neuronal excitability and anticonvulsant activity.
METHODS: We applied high-throughput screening to identify ligands able to modulate the Kv1.1-T1 domain/Kvβ1 protein complex. We then selected a compound that was characterized on recombinant Kv1.1/Kvβ1 channels by electrophysiology and further evaluated on sustained neuronal firing and on in vitro epileptiform activity using a high K+ -low Ca2+ model in hippocampal slices.
RESULTS: We identified a novel compound able to modulate the interaction of the Kv1.1/Kvβ1 complex and that produced a functional inhibition of Kv1.1/Kvβ1 channel inactivation. We demonstrated that this compound reduced the sustained repetitive firing in hippocampal neurons and was able to abolish the development of in vitro epileptiform activity.
CONCLUSIONS: This study describes a rational drug discovery approach for the identification of novel ligands that inhibit Kv1.1 channel inactivation and provides pharmacological evidence that such a mechanism translates into physiological effects by reducing in vitro epileptiform activity.
Begum,
Action potential broadening in a presynaptic channelopathy.
2016, Pubmed
Begum,
Action potential broadening in a presynaptic channelopathy.
2016,
Pubmed
Browne,
Episodic ataxia/myokymia syndrome is associated with point mutations in the human potassium channel gene, KCNA1.
1994,
Pubmed
Errington,
The investigational anticonvulsant lacosamide selectively enhances slow inactivation of voltage-gated sodium channels.
2008,
Pubmed
Goldberg,
K+ channels at the axon initial segment dampen near-threshold excitability of neocortical fast-spiking GABAergic interneurons.
2008,
Pubmed
Grosse,
Expression of Kv1 potassium channels in mouse hippocampal primary cultures: development and activity-dependent regulation.
2000,
Pubmed
Gulbis,
Structure of the cytoplasmic beta subunit-T1 assembly of voltage-dependent K+ channels.
2000,
Pubmed
,
Xenbase
Heeroma,
Episodic ataxia type 1 mutations differentially affect neuronal excitability and transmitter release.
2009,
Pubmed
Hille,
Ionic selectivity of Na and K channels of nerve membranes.
1975,
Pubmed
Hsiao,
Participation of Kv1 channels in control of membrane excitability and burst generation in mesencephalic V neurons.
2009,
Pubmed
Humphrey,
VMD: visual molecular dynamics.
1996,
Pubmed
Imbrici,
Episodic ataxia type 1 mutations affect fast inactivation of K+ channels by a reduction in either subunit surface expression or affinity for inactivation domain.
2011,
Pubmed
,
Xenbase
Ishida,
Kcna1-mutant rats dominantly display myokymia, neuromyotonia and spontaneous epileptic seizures.
2012,
Pubmed
,
Xenbase
Jnoff,
Binding mode and structure-activity relationships around direct inhibitors of the Nrf2-Keap1 complex.
2014,
Pubmed
Li,
Neuregulin 1 regulates excitability of fast-spiking neurons through Kv1.1 and acts in epilepsy.
2011,
Pubmed
Lu,
Disruption of Kv1.1 N-type inactivation by novel small molecule inhibitors (disinactivators).
2008,
Pubmed
Lynch,
The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam.
2004,
Pubmed
Margineanu,
Inhibition of neuronal hypersynchrony in vitro differentiates levetiracetam from classical antiepileptic drugs.
2000,
Pubmed
McLean,
Carbamazepine and 10,11-epoxycarbamazepine produce use- and voltage-dependent limitation of rapidly firing action potentials of mouse central neurons in cell culture.
1986,
Pubmed
Meiri,
Reversible antisense inhibition of Shaker-like Kv1.1 potassium channel expression impairs associative memory in mouse and rat.
1997,
Pubmed
Niespodziany,
Desynchronizing effect of levetiracetam on epileptiform responses in rat hippocampal slices.
2003,
Pubmed
Niespodziany,
Brivaracetam differentially affects voltage-gated sodium currents without impairing sustained repetitive firing in neurons.
2015,
Pubmed
Niespodziany,
Discovery of a small molecule modulator of the Kv1.1/Kvβ1 channel complex that reduces neuronal excitability and in vitro epileptiform activity.
2020,
Pubmed
,
Xenbase
Ovsepian,
Distinctive role of KV1.1 subunit in the biology and functions of low threshold K(+) channels with implications for neurological disease.
2016,
Pubmed
Pan,
Potentiation of the Kv1 family K(+) channel by cortisone analogues.
2012,
Pubmed
Pan,
Cortisone dissociates the Shaker family K+ channels from their beta subunits.
2008,
Pubmed
,
Xenbase
Pongs,
Ancillary subunits associated with voltage-dependent K+ channels.
2010,
Pubmed
Schreier,
NMR assignments of a 48 kDa tetramer of the T1 domain of the mammalian voltage gated potassium channel Kv1.4.
2009,
Pubmed
Schulte,
The epilepsy-linked Lgi1 protein assembles into presynaptic Kv1 channels and inhibits inactivation by Kvbeta1.
2006,
Pubmed
,
Xenbase
Simeone,
Loss of the Kv1.1 potassium channel promotes pathologic sharp waves and high frequency oscillations in in vitro hippocampal slices.
2013,
Pubmed
Smart,
Deletion of the K(V)1.1 potassium channel causes epilepsy in mice.
1998,
Pubmed
Sosanya,
Rapamycin reveals an mTOR-independent repression of Kv1.1 expression during epileptogenesis.
2015,
Pubmed
Strang,
A central role for the T1 domain in voltage-gated potassium channel formation and function.
2001,
Pubmed
Tang,
A high-throughput screening method for small-molecule inhibitors of the aberrant mutant SOD1 and dynein complex interaction.
2012,
Pubmed
Torres,
A marriage of convenience: beta-subunits and voltage-dependent K+ channels.
2007,
Pubmed
Verma-Kurvari,
Regional and cellular expression patterns of four K+ channel mRNAs in the adult rat brain.
1997,
Pubmed
Wang,
Localization of Kv1.1 and Kv1.2, two K channel proteins, to synaptic terminals, somata, and dendrites in the mouse brain.
1994,
Pubmed
Wykes,
Optogenetic and potassium channel gene therapy in a rodent model of focal neocortical epilepsy.
2012,
Pubmed
Zhang,
Disinactivation of N-type inactivation of voltage-gated K channels by an erbstatin analogue.
2004,
Pubmed
,
Xenbase
