更新于：2024-11-01

KCNN4 x SK channel

更新于：2024-11-01

基本信息

关联

项与 KCNN4 x SK channel 相关的药物

NS4591

靶点

KCNN4 x SK channel

作用机制

KCNN4 modulators [+1]

在研机构

NTG Nordic Transport Group A/S

原研机构

NTG Nordic Transport Group A/S

在研适应症

膀胱过度活动症

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 KCNN4 x SK channel 相关的临床结果

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100 项与 KCNN4 x SK channel 相关的转化医学

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0 项与 KCNN4 x SK channel 相关的专利（医药）

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项与 KCNN4 x SK channel 相关的文献（医药）

2023-11-01·American Journal of Physiology-Gastrointestinal and Liver Physiology

K_V7 but not dual small and intermediate K_Ca channel openers inhibit the activation of colonic afferents by noxious stimuli

Article

作者: Higham, James P. ; Raine, Tim ; Bhebhe, Charity N. ; Gupta, Rohit A. ; Bulmer, David C.

Despite marked coexpression of small ( Kcnn1, Kcnn2) and intermediate ( Kcnn4) conductance calcium-activated potassium channel transcripts with P2X3 ( P2rx3) or bradykinin B2 ( Bdkrb2) receptors in colonic sensory neurons, pharmacological activation of these channels had no effect on the colonic afferent response to ATP, bradykinin or luminal distension of the colon. This is in contrast to the robust inhibitory effect of the KV7 channel opener, retigabine.

2023-02-01·Journal of Biological Chemistry

Molecular dynamics simulations of the calmodulin-induced α-helix in the SK2 calcium-gated potassium ion channel

Article

作者: Muguruza-Montero, Arantza ; Bergara, Aitor ; Ramis, Rafael ; Núñez, Eider ; Ballesteros, Óscar R ; Villarroel, Álvaro ; M-Alicante, Sara ; Leonardo, Aritz

The family of small-conductance Ca²⁺-activated potassium ion channels (SK channels) is composed of four members (SK1, SK2, SK3, and SK4) involved in neuron-firing regulation. The gating of these channels depends on the intracellular Ca²⁺ concentration, and their sensitivity to this ion is provided by calmodulin (CaM). This protein binds to a specific region in SK channels known as the calmodulin-binding domain (CaMBD), an event which is essential for their gating. While CaMBDs are typically disordered in the absence of CaM, the SK2 channel subtype displays a small prefolded α-helical region in its CaMBD even if CaM is not present. This small helix is known to turn into a full α-helix upon CaM binding, although the molecular-level details for this conversion are not fully understood yet. In this work, we offer new insights on this physiologically relevant process by means of enhanced sampling, atomistic Hamiltonian replica exchange molecular dynamics simulations, providing a more detailed understanding of CaM binding to this target. Our results show that CaM is necessary for inducing a full α-helix along the SK2 CaMBD through hydrophobic interactions with V426 and L427. However, it is also necessary that W431 does not compete for these interactions; the role of the small prefolded α-helix in the SK2 CaMBD would be to stabilize W431 so that this is the case. In conclusion, our findings provide further insight into a key interaction between CaM and SK channels that is important for channel sensitivity to Ca²⁺.

2023-01-01·Cardiovascular therapeutics

KCa3.1 Promotes Proinflammatory Exosome Secretion by Activating AKT/Rab27a in Atrial Myocytes during Rapid Pacing.

Article

作者: He, Shanqing ; Fu, Yuntao ; Yang, Mei ; Yao, Yajun ; Zhao, Qingyan ; Wang, Youcheng ; Liu, Dishiwen ; Cao, Zhen ; Wang, Xuewen ; Chen, Huiyu

PurposeThe aim of this study was to investigate the role of the medium-conductance calcium-activated potassium channel (KCNN4, KCa3.1) in the secretion of proinflammatory exosomes by atrial myocytes.MethodsEighteen beagles were randomly divided into the sham group (n = 6), pacing group (n = 6), and pacing+TRAM-34 group (n = 6). Electrophysiological data, such as the effective refractory period, atrial fibrillation (AF) induction, and AF duration, were collected by programmed stimulation. Atrial tissues were subjected to hematoxylin and eosin, Masson's trichrome, and immunofluorescence staining. The expression of KCa3.1 and Rab27a was assessed by immunohistochemistry and western blotting. The downstream signaling pathways involved in KCa3.1 were examined by rapid pacing or overexpressing KCNN4 in HL-1 cells.ResultsAtrial rapid pacing significantly induced electrical remodeling, inflammation, fibrosis, and exosome secretion in the canine atrium, while TRAM-34 (KCa3.1 blocker) inhibited these changes. Compared with those in control HL-1 cells, the levels of exosome markers and inflammatory factors were increased in pacing HL-1 cells. Furthermore, the levels of CD68 and iNOS in macrophages incubated with exosomes derived from HL-1 cells were higher in the pacing-exo group than in the control group. More importantly, KCa3.1 regulated exosome secretion through the AKT/Rab27a signaling pathway. Similarly, inhibiting the downstream signaling pathway of KCa3.1 significantly inhibited exosome secretion.ConclusionsKCa3.1 promotes proinflammatory exosome secretion through the AKT/Rab27a signaling pathway. Inhibiting the KCa3.1/AKT/Rab27a signaling pathway reduces myocardial tissue structural remodeling in AF.