更新于：2024-11-01

KCNN2 x KCa2.3

更新于：2024-11-01

基本信息

关联

项与 KCNN2 x KCa2.3 相关的药物

NSD-8011

靶点

KCNN2 x KCa2.3

作用机制

KCNN2 inhibitors [+1]

在研机构

Cadent Therapeutics, Inc.

原研机构

NTG Nordic Transport Group A/S

在研适应症

共济失调

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 KCNN2 x KCa2.3 相关的临床结果

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100 项与 KCNN2 x KCa2.3 相关的转化医学

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0 项与 KCNN2 x KCa2.3 相关的专利（医药）

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项与 KCNN2 x KCa2.3 相关的文献（医药）

2023-11-01·Journal of neuroscience research

K_Ca 2.2 (KCNN2): A physiologically and therapeutically important potassium channel.

Review

作者: Naguib, Nadeen ; Zhang, Miao ; Lam, Elyn ; Nam, Young-Woo ; Orfali, Razan ; Rahman, Mohammad Asikur ; Dave, Nikita

One group of the K⁺ ion channels, the small-conductance Ca²⁺ -activated potassium channels (K_Ca 2.x, also known as SK channels family), is widely expressed in neurons as well as the heart, endothelial cells, etc. They are named small-conductance Ca²⁺ -activated potassium channels (SK channels) due to their comparatively low single-channel conductance of about ~10 pS. These channels are insensitive to changes in membrane potential and are activated solely by rises in the intracellular Ca²⁺ . According to the phylogenic research done on the K_Ca 2.x channels family, there are three channels' subtypes: K_Ca 2.1, K_Ca 2.2, and K_Ca 2.3, which are encoded by KCNN1, KCNN2, and KCNN3 genes, respectively. The K_Ca 2.x channels regulate neuronal excitability and responsiveness to synaptic input patterns. K_Ca 2.x channels inhibit excitatory postsynaptic potentials (EPSPs) in neuronal dendrites and contribute to the medium afterhyperpolarization (mAHP) that follows the action potential bursts. Multiple brain regions, including the hippocampus, express the K_Ca 2.2 channel encoded by the KCNN2 gene on chromosome 5. Of particular interest, rat cerebellar Purkinje cells express K_Ca 2.2 channels, which are crucial for various cellular processes during development and maturation. Patients with a loss-of-function of KCNN2 mutations typically exhibit extrapyramidal symptoms, cerebellar ataxia, motor and language developmental delays, and intellectual disabilities. Studies have revealed that autosomal dominant neurodevelopmental movement disorders resembling rodent symptoms are caused by heterozygous loss-of-function mutations, which are most likely to induce KCNN2 haploinsufficiency. The K_Ca 2.2 channel is a promising drug target for spinocerebellar ataxias (SCAs). SCAs exhibit the dysregulation of firing in cerebellar Purkinje cells which is one of the first signs of pathology. Thus, selective K_Ca 2.2 modulators are promising potential therapeutics for SCAs.

2023-06-19·Philosophical transactions of the Royal Society of London. Series B, Biological sciences

Small-conductance calcium-activated potassium channels in the heart: expression, regulation and pathological implications.

Review

作者: Xu, Dandi ; Tan, Xiaoqiu ; Liu, Ting ; Wang, Yan ; Zhou, Yafei ; Huang, Christopher L-H ; Li, Tao ; Wan, Juyi

Ca²⁺-activated K⁺ channels are critical to cellular Ca²⁺ homeostasis and excitability; they couple intracellular Ca²⁺ and membrane voltage change. Of these, the small, 4-14 pS, conductance SK channels include three, KCNN1-3 encoded, SK1/KCa2.1, SK2/KCa2.2 and SK3/KCa2.3, channel subtypes with characteristic, EC₅₀ ∼ 10 nM, 40 pM, 1 nM, apamin sensitivities. All SK channels, particularly SK2 channels, are expressed in atrial, ventricular and conducting system cardiomyocytes. Pharmacological and genetic modification results have suggested that SK channel block or knockout prolonged action potential durations (APDs) and effective refractory periods (ERPs) particularly in atrial, but also in ventricular, and sinoatrial, atrioventricular node and Purkinje myocytes, correspondingly affect arrhythmic tendency. Additionally, mitochondrial SK channels may decrease mitochondrial Ca²⁺ overload and reactive oxygen species generation. SK channels show low voltage but marked Ca²⁺ dependences (EC₅₀ ∼ 300-500 nM) reflecting their α-subunit calmodulin (CaM) binding domains, through which they may be activated by voltage-gated or ryanodine-receptor Ca²⁺ channel activity. SK function also depends upon complex trafficking and expression processes and associations with other ion channels or subunits from different SK subtypes. Atrial and ventricular clinical arrhythmogenesis may follow both increased or decreased SK expression through decreased or increased APD correspondingly accelerating and stabilizing re-entrant rotors or increasing incidences of triggered activity. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.

2023-02-01·Acta Pharmacologica Sinica

Channelopathy of small- and intermediate-conductance Ca2+-activated K+ channels

Review

作者: Downey, Myles ; Zhang, Miao ; Rahman, Mohammad Asikur ; Nam, Young-Woo ; Cui, Meng

Small- and intermediate-conductance Ca²⁺-activated K⁺ (K_Ca2.x/K_Ca3.1 also called SK/IK) channels are gated exclusively by intracellular Ca²⁺. The Ca²⁺ binding protein calmodulin confers sub-micromolar Ca²⁺ sensitivity to the channel-calmodulin complex. The calmodulin C-lobe is constitutively associated with the proximal C-terminus of the channel. Interactions between calmodulin N-lobe and the channel S4-S5 linker are Ca²⁺-dependent, which subsequently trigger conformational changes in the channel pore and open the gate. KCNN genes encode four subtypes, including KCNN1 for K_Ca2.1 (SK1), KCNN2 for K_Ca2.2 (SK2), KCNN3 for K_Ca2.3 (SK3), and KCNN4 for K_Ca3.1 (IK). The three K_Ca2.x channel subtypes are expressed in the central nervous system and the heart. The K_Ca3.1 subtype is expressed in the erythrocytes and the lymphocytes, among other peripheral tissues. The impact of dysfunctional K_Ca2.x/K_Ca3.1 channels on human health has not been well documented. Human loss-of-function K_Ca2.2 mutations have been linked with neurodevelopmental disorders. Human gain-of-function mutations that increase the apparent Ca²⁺ sensitivity of K_Ca2.3 and K_Ca3.1 channels have been associated with Zimmermann-Laband syndrome and hereditary xerocytosis, respectively. This review article discusses the physiological significance of K_Ca2.x/K_Ca3.1 channels, the pathophysiology of the diseases linked with K_Ca2.x/K_Ca3.1 mutations, the structure-function relationship of the mutant K_Ca2.x/K_Ca3.1 channels, and potential pharmacological therapeutics for the K_Ca2.x/K_Ca3.1 channelopathy.