更新于：2024-11-01

Kv3.2 x Kv3.1

更新于：2024-11-01

基本信息

关联

项与 Kv3.2 x Kv3.1 相关的药物

Kv 3.1/3.2 activator (Bionomics)

靶点

Kv3.1 x Kv3.2

作用机制

Kv3.1 agonists [+1]

在研机构

Bioneer, Inc.

原研机构

Bioneer, Inc.

在研适应症

认知障碍

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 Kv3.2 x Kv3.1 相关的临床结果

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100 项与 Kv3.2 x Kv3.1 相关的转化医学

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0 项与 Kv3.2 x Kv3.1 相关的专利（医药）

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项与 Kv3.2 x Kv3.1 相关的文献（医药）

2024-03-01·Clinical EEG and Neuroscience

Gamma Oscillations and Potassium Channel Modulation in Schizophrenia: Targeting GABAergic Dysfunction

Article

作者: Kaar, Stephen J. ; Howes, Oliver D. ; Nottage, Judith F. ; Angelescu, Ilinca ; Marques, Tiago Reis

Impairments in gamma-aminobutyric acid (GABAergic) interneuron function lead to gamma power abnormalities and are thought to underlie symptoms in people with schizophrenia. Voltage-gated potassium 3.1 (Kv3.1) and 3.2 (Kv3.2) channels on GABAergic interneurons are critical to the generation of gamma oscillations suggesting that targeting Kv3.1/3.2 could augment GABAergic function and modulate gamma oscillation generation. Here, we studied the effect of a novel potassium Kv3.1/3.2 channel modulator, AUT00206, on resting state frontal gamma power in people with schizophrenia. We found a significant positive correlation between frontal resting gamma (35–45 Hz) power ( n = 22, r = 0.613, P < .002) and positive and negative syndrome scale (PANSS) positive symptom severity. We also found a significant reduction in frontal gamma power ( t13 = 3.635, P = .003) from baseline in patients who received AUT00206. This provides initial evidence that the Kv3.1/3.2 potassium channel modulator, AUT00206, may address gamma oscillation abnormalities in schizophrenia.

2024-01-16·Proceedings of the National Academy of Sciences1区 · 综合性期刊

A structurally precise mechanism links an epilepsy-associated KCNC2 potassium channel mutation to interneuron dysfunction

1区 · 综合性期刊

Article

作者: Massey, Shavonne L. ; Pipatpolkai, Tanadet ; Delemotte, Lucie ; Clatot, Jerome ; Covarrubias, Manuel ; Liang, Qiansheng ; Vogels, Tim P. ; Goldberg, Ethan M. ; Helbig, Ingo ; Currin, Christopher B.

De novo heterozygous variants in KCNC2 encoding the voltage-gated potassium (K + ) channel subunit Kv3.2 are a recently described cause of developmental and epileptic encephalopathy (DEE). A de novo variant in KCNC2 c.374G > A (p.Cys125Tyr) was identified via exome sequencing in a patient with DEE. Relative to wild-type Kv3.2, Kv3.2-p.Cys125Tyr induces K + currents exhibiting a large hyperpolarizing shift in the voltage dependence of activation, accelerated activation, and delayed deactivation consistent with a relative stabilization of the open conformation, along with increased current density. Leveraging the cryogenic electron microscopy (cryo-EM) structure of Kv3.1, molecular dynamic simulations suggest that a strong π-π stacking interaction between the variant Tyr125 and Tyr156 in the α-6 helix of the T1 domain promotes a relative stabilization of the open conformation of the channel, which underlies the observed gain of function. A multicompartment computational model of a Kv3-expressing parvalbumin-positive cerebral cortex fast-spiking γ-aminobutyric acidergic (GABAergic) interneuron (PV-IN) demonstrates how the Kv3.2-Cys125Tyr variant impairs neuronal excitability and dysregulates inhibition in cerebral cortex circuits to explain the resulting epilepsy.

2022-10-01·Psychopharmacology

The effects of AUT00206, a novel Kv3.1/3.2 potassium channel modulator, on task-based reward system activation: a test of mechanism in schizophrenia

Article

作者: McGuire, Philip ; Howes, Oliver D ; Angelescu, Ilinca ; Sajjala, Anil ; Large, Charles ; Marques, Tiago Reis ; Hutchison, John ; Nour, Matthew M ; Sharman, Alice ; Kaar, Stephen J

AbstractThe pathophysiology of schizophrenia involves abnormal reward processing, thought to be due to disrupted striatal and dopaminergic function. Consistent with this hypothesis, functional magnetic resonance imaging (fMRI) studies using the monetary incentive delay (MID) task report hypoactivation in the striatum during reward anticipation in schizophrenia. Dopamine neuron activity is modulated by striatal GABAergic interneurons. GABAergic interneuron firing rates, in turn, are related to conductances in voltage-gated potassium 3.1 (Kv3.1) and 3.2 (Kv3.2) channels, suggesting that targeting Kv3.1/3.2 could augment striatal function during reward processing. Here, we studied the effect of a novel potassium Kv3.1/3.2 channel modulator, AUT00206, on striatal activation in patients with schizophrenia, using the MID task. Each participant completed the MID during fMRI scanning on two occasions: once at baseline, and again following either 4 weeks of AUT00206 or placebo treatment. We found a significant inverse relationship at baseline between symptom severity and reward anticipation-related neural activation in the right associative striatum (r = -0.461, p = 0.035). Following treatment with AUT00206, there was a significant increase in reward anticipation-related activation in the left associative striatum (t(13) = 4.23, peak-level p(FWE) < 0.05)), but no significant effect in the ventral striatum. This provides preliminary evidence that the Kv3.1/3.2 potassium channel modulator, AUT00206, may address reward-related striatal abnormalities in schizophrenia.