更新于：2024-11-01

Kir3.2 x Kir3.1

更新于：2024-11-01

基本信息

关联

项与 Kir3.2 x Kir3.1 相关的药物

GAT1508

靶点

Kir3.1 x Kir3.2

作用机制

Kir3.1 激活剂 [+1]

在研机构

Northeastern University

原研机构

Northeastern University

在研适应症

创伤后应激障碍

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 Kir3.2 x Kir3.1 相关的临床结果

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100 项与 Kir3.2 x Kir3.1 相关的转化医学

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0 项与 Kir3.2 x Kir3.1 相关的专利（医药）

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187

项与 Kir3.2 x Kir3.1 相关的文献（医药）

2024-10-01·Molecules and Cells

Cellular and metabolic function of GIRK1 potassium channels expressed by arcuate POMC and NPY/AgRP neurons

Article

作者: Sohn, Jong-Woo ; Choi, Yeeun ; Yoo, Eun-Seon ; Oh, Youjin

It is well known that the G protein-gated inwardly rectifying K⁺ (GIRK) channels are critical to maintain excitability of central neurons. GIRK channels consist of 4 subunits and GIRK1/GIRK2 heterotetramers are considered to be the neuronal prototype. We previously reported the metabolic significance of GIRK2 subunits expressed by the neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons of the arcuate nucleus of the hypothalamus (ARH). However, the role of GIRK1 subunits expressed by the neurons of ARH remains to be determined. In this study, we delineated the contribution of GIRK1 channel subunits to the excitability of the pro-opiomelanocortin (POMC) and NPY/AgRP neurons of the ARH. We further assessed the metabolic function of GIRK1 subunits expressed by these neurons. Our results provide insight how GIRK channels regulate arcuate POMC and NPY/AgRP neurons and shape metabolic phenotypes.

2024-05-01·Journal of Biological Chemistry

Structural determinants of the direct inhibition of GIRK channels by Sigma-1 receptor antagonist

Article

作者: Kubo, Yoshihiro ; Tateyama, Michihiro ; Liu, Chang ; Chen, I-Shan

G-protein-gated inward rectifier K⁺ (GIRK) channels play a critical role in the regulation of the excitability of cardiomyocytes and neurons and include GIRK1, GIRK2, GIRK3 and GIRK4 subfamily members. BD1047 dihydrobromide (BD1047) is one of the representative antagonists of the multifunctional Sigma-1 receptor (S1R). In the analysis of the effect of BD1047 on the regulation of Gi-coupled receptors by S1R using GIRK channel as an effector, we observed that BD1047, as well as BD1063, directly inhibited GIRK currents even in the absence of S1R and in a voltage-independent manner. Thus, we aimed to clarify the effect of BD1047 on GIRK channels and identify the structural determinants. By electrophysiological recordings in Xenopus oocytes, we observed that BD1047 directly inhibited GIRK channel currents, producing a much stronger inhibition of GIRK4 compared to GIRK2. It also inhibited ACh-induced native GIRK current in isolated rat atrial myocytes. Chimeric and mutagenesis studies of GIRK2 and GIRK4 combined with molecular docking analysis demonstrated the importance of Leu77 and Leu84 within the cytoplasmic, proximal N-terminal region and Glu147 within the pore-forming region of GIRK4 for inhibition by BD1047. The activator of GIRK channels, ivermectin, competed with BD1047 at Leu77 on GIRK4. This study provides us with a novel inhibitor of GIRK channels and information for developing pharmacological treatments for GIRK4-associated diseases.

2024-01-01·Biochimica et Biophysica Acta (BBA) - Biomembranes

Structural insights in the permeation mechanism of an activated GIRK2 channel

Article

作者: Wang, Lei ; Shi, Dingyuan ; Li, Dailin

G protein-gated inwardly rectifying potassium (GIRK) channels play a significant role in physiopathology by the regulation of cell excitability. This regulation depends on the K⁺ ion conduction induced by structural constrictions: the selectivity filters (SFs), helix bundle crossings (HBCs), and G-loop gates. To explore why no permeation occurred when the constrictions were kept in the open state, a 4-K⁺-related occupancy mechanism was proposed. Unfortunately, this hypothesis was neither assessed, nor was the energetic characteristics presented. To identify the permeation mechanism on an atomic level, all-atom molecular dynamic (MD) simulations and a coupled quantum mechanics and molecular mechanics (QM/MM) method were used for the GIRK2 mutant R201A. It was found that the R201A had a moderate conductive capability in the presence of PIP₂. Furthermore, the 4-K⁺ group of ions was found to dominate the conduction through the activated HBC gate. This shielding-like mechanism was assessed by the potential energy barrier along the conduction pathway. Mutation studies did further support the assumption that E152 was responsible for the mechanism. Moreover, E152 was most probably facilitating the inflow of ions from the SF to the cavity. On the contrary, N184 had no remarkable effect on this mechanism, except for the conduction efficiency. These findings highlighted the necessity of a multi-ion distribution for the conduction to take place, and indicated that the K⁺ migration was not only determined by the channel conductive state in the GIRK channel. The here presented multi-ion permeation mechanism may help to provide an effective way to regulate the channelopathies.