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.
J Pharmacol Exp Ther
2020 Jun 01;3733:391-401. doi: 10.1124/jpet.119.264507.
Show Gene links
Show Anatomy links
Isoform-Selective KCNA1 Potassium Channel Openers Built from Glycine.
Manville RW, Abbott GW.
???displayArticle.abstract???
Loss of function of voltage-gated potassium (Kv) channels is linked to a range of lethal or debilitating channelopathies. New pharmacological approaches are warranted to isoform-selectively activate specific Kv channels. One example is KCNA1 Potassium Voltage-Gated Channel Subfamily A Member 1 (KCNA1) (Kv1.1), an archetypal Shaker-type Kv channel, in which loss-of-function mutations cause episodic ataxia type 1 (EA1). EA1 causes constant myokomia and episodic bouts of ataxia and may associate with epilepsy and other disorders. We previously found that the inhibitory neurotransmitter γ-aminobutyric acid and modified versions of glycine directly activate Kv channels within the KCNQ subfamily, a characteristic favored by strong negative electrostatic surface potential near the neurotransmitter carbonyl group. Here, we report that adjusting the number and positioning of fluorine atoms within the fluorophenyl ring of glycine derivatives produces isoform-selective KCNA1 channel openers that are inactive against KCNQ2/3 channels, or even KCNA2, the closest relative of KCNA1. The findings refine our understanding of the molecular basis for KCNQ versus KCNA1 activation and isoform selectivity and constitute, to our knowledge, the first reported isoform-selective KCNA1 opener. SIGNIFICANCE STATEMENT: Inherited loss-of-function gene sequence variants in KCNA1, which encodes the KCNA1 (Kv1.1) voltage-gated potassium channel, cause episodic ataxia type 1 (EA1), a movement disorder also linked to epilepsy and developmental delay. We have discovered several isoform-specific KCNA1-activating small molecules, addressing a notable gap in the field and providing possible lead compounds and a novel chemical space for the development of potential future therapeutic drugs for EA1.
Anderson,
Allele-Selective Knockdown of MYH7 Using Antisense Oligonucleotides.
2020, Pubmed
Anderson,
Allele-Selective Knockdown of MYH7 Using Antisense Oligonucleotides.
2020,
Pubmed Browne,
Episodic ataxia/myokymia syndrome is associated with point mutations in the human potassium channel gene, KCNA1.
1994,
Pubmed Chen,
Functional analysis of a novel potassium channel (KCNA1) mutation in hereditary myokymia.
2007,
Pubmed
,
Xenbase Corbett,
Dominant KCNA2 mutation causes episodic ataxia and pharmacoresponsive epilepsy.
2016,
Pubmed
,
Xenbase Crump,
Arrhythmogenic KCNE gene variants: current knowledge and future challenges.
2014,
Pubmed D'Adamo,
Novel phenotype associated with a mutation in the KCNA1(Kv1.1) gene.
2014,
Pubmed D'Adamo,
New insights into the pathogenesis and therapeutics of episodic ataxia type 1.
2015,
Pubmed D'Adamo,
Episodic ataxia type-1 mutations in the hKv1.1 cytoplasmic pore region alter the gating properties of the channel.
1998,
Pubmed
,
Xenbase Demos,
A novel KCNA1 mutation associated with global delay and persistent cerebellar dysfunction.
2009,
Pubmed De Silva,
Deconstruction of an African folk medicine uncovers a novel molecular strategy for therapeutic potassium channel activation.
2018,
Pubmed
,
Xenbase Eunson,
Clinical, genetic, and expression studies of mutations in the potassium channel gene KCNA1 reveal new phenotypic variability.
2000,
Pubmed Glaudemans,
A missense mutation in the Kv1.1 voltage-gated potassium channel-encoding gene KCNA1 is linked to human autosomal dominant hypomagnesemia.
2009,
Pubmed Helbig,
A recurrent mutation in KCNA2 as a novel cause of hereditary spastic paraplegia and ataxia.
2016,
Pubmed
,
Xenbase Imbrici,
A novel KCNA1 mutation in a patient with paroxysmal ataxia, myokymia, painful contractures and metabolic dysfunctions.
2017,
Pubmed Ishida,
Kcna1-mutant rats dominantly display myokymia, neuromyotonia and spontaneous epileptic seizures.
2012,
Pubmed
,
Xenbase Jan,
Voltage-gated potassium channels and the diversity of electrical signalling.
2012,
Pubmed Karalok,
Identification of a New de Novo Mutation Underlying Regressive Episodic Ataxia Type I.
2018,
Pubmed Kim,
Atomic basis for therapeutic activation of neuronal potassium channels.
2015,
Pubmed
,
Xenbase Kinali,
Expanding the phenotype of potassium channelopathy: severe neuromyotonia and skeletal deformities without prominent Episodic Ataxia.
2004,
Pubmed Lange,
Refinement of the binding site and mode of action of the anticonvulsant Retigabine on KCNQ K+ channels.
2009,
Pubmed
,
Xenbase Manville,
Gabapentin Is a Potent Activator of KCNQ3 and KCNQ5 Potassium Channels.
2018,
Pubmed
,
Xenbase Manville,
In silico re-engineering of a neurotransmitter to activate KCNQ potassium channels in an isoform-specific manner.
2019,
Pubmed
,
Xenbase Manville,
KCNQ5 activation is a unifying molecular mechanism shared by genetically and culturally diverse botanical hypotensive folk medicines.
2019,
Pubmed Manville,
Cilantro leaf harbors a potent potassium channel-activating anticonvulsant.
2019,
Pubmed
,
Xenbase Manville,
Direct neurotransmitter activation of voltage-gated potassium channels.
2018,
Pubmed
,
Xenbase Ptácek,
Molecular biology of episodic movement disorders.
2002,
Pubmed Roepke,
Pharmacogenetics and cardiac ion channels.
2006,
Pubmed Sakamoto,
Molecular mechanisms underlying pimaric acid-induced modulation of voltage-gated K+ channels.
2017,
Pubmed Spauschus,
Functional characterization of a novel mutation in KCNA1 in episodic ataxia type 1 associated with epilepsy.
1999,
Pubmed
,
Xenbase Syrbe,
De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy.
2015,
Pubmed van der Wijst,
A de novo KCNA1 Mutation in a Patient with Tetany and Hypomagnesemia.
2018,
Pubmed van der Wijst,
Functional analysis of the Kv1.1 N255D mutation associated with autosomal dominant hypomagnesemia.
2010,
Pubmed Verdura,
Complete loss of KCNA1 activity causes neonatal epileptic encephalopathy and dyskinesia.
2020,
Pubmed Wuttke,
The new anticonvulsant retigabine favors voltage-dependent opening of the Kv7.2 (KCNQ2) channel by binding to its activation gate.
2005,
Pubmed
,
Xenbase
