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调节门控和齿轮：LRRC26（ ）亚基调节BK通道的内在门控和电压传感器偶联。

Tuning the gate and the gear: The LRRC26 ( ) subunit modulates intrinsic gating and voltage-sensor coupling of the BK channel.

作者信息

Echeverria Felipe, Peña-Pichicoi Antonio, Fernandez Miguel, Carrasquel-Ursulaez Willy, Castillo Juan P, Alvarez Osvaldo, Latorre Ramon

机构信息

Centro Interdisciplinario de Neurociencia. Instituto de Neurociencia, Facultad de Ciencias, Universidad de Valparaíso Pasaje Harrington 287, Valparaíso 2340000, Chile.

Doctorado en Ciencias Mención Biofísica y Biología Computacional, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile.

出版信息

bioRxiv. 2025 Sep 6:2025.09.04.674290. doi: 10.1101/2025.09.04.674290.

DOI:10.1101/2025.09.04.674290
PMID:40950215
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12424821/
Abstract

Association of auxiliary subunits ( and ) with the pore-forming subunit of the calcium-and voltage-activated potassium (BK) channel provides functional diversity. promotes a significant leftward shift of the voltage activation curve, ensuring the adequate functioning of secretory glands, allowing the BK channel to release at the cell's resting concentration. Given its physiological importance, it is crucial to elucidate the mechanisms of action. However, structural and functional studies have yielded conflicting conclusions regarding the modulation of BK channels by . Here, using macroscopic, single-channel, and gating current measurements, we demonstrate that at zero mV increases 92-fold the equilibrium constant that defines the closed-open transition by destabilizing the channel's closed configuration and enhancing the coupling between the voltage sensor and the pore domain, without affecting voltage-sensor activation. These results suggest that not only causes an increase in the energetic coupling between the voltage sensors and the pore but mainly enhances the channel opening reaction.

摘要

辅助亚基（ 和 ）与钙激活和电压激活钾（BK）通道的成孔 亚基结合，可提供功能多样性。 促使电压激活曲线显著左移，确保分泌腺的正常功能，使BK通道在细胞静息 浓度下释放 。鉴于其生理重要性，阐明其作用机制至关重要。然而，关于 通过何种方式调节BK通道，结构和功能研究得出了相互矛盾的结论。在这里，我们通过宏观、单通道和门控电流测量表明，在零毫伏时， 通过破坏通道的关闭构型并增强电压传感器与孔结构域之间的耦合，使定义关闭 - 开放转变的平衡常数增加了92倍，而不影响电压传感器的激活。这些结果表明， 不仅导致电压传感器与孔之间的能量耦合增加，而且主要增强了通道开放反应。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b4d7/12424821/6e9ac0cda42d/nihpp-2025.09.04.674290v1-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b4d7/12424821/750091bb546e/nihpp-2025.09.04.674290v1-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b4d7/12424821/87e57b9df6bb/nihpp-2025.09.04.674290v1-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b4d7/12424821/b3668c291951/nihpp-2025.09.04.674290v1-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b4d7/12424821/b216ca4fd498/nihpp-2025.09.04.674290v1-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b4d7/12424821/6e9ac0cda42d/nihpp-2025.09.04.674290v1-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b4d7/12424821/750091bb546e/nihpp-2025.09.04.674290v1-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b4d7/12424821/87e57b9df6bb/nihpp-2025.09.04.674290v1-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b4d7/12424821/b3668c291951/nihpp-2025.09.04.674290v1-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b4d7/12424821/b216ca4fd498/nihpp-2025.09.04.674290v1-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b4d7/12424821/6e9ac0cda42d/nihpp-2025.09.04.674290v1-f0005.jpg

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本文引用的文献

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Cryo-EM structure of the Slo1 potassium channel with the auxiliary γ1 subunit suggests a mechanism for depolarization-independent activation.冷冻电镜结构解析揭示 Slo1 钾通道与辅助 γ1 亚基的作用机制，提示去极化非依赖性激活的可能性。
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2
Dual allosteric modulation of voltage and calcium sensitivities of the Slo1-LRRC channel complex.Slo1-LRRC 通道复合物的电压和钙敏感性的双重变构调节。
Mol Cell. 2023 Dec 21;83(24):4555-4569.e4. doi: 10.1016/j.molcel.2023.11.005. Epub 2023 Nov 29.
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Subunits of BK channels promote breast cancer development and modulate responses to endocrine treatment in preclinical models.
大电导钙激活钾通道（BK通道）的亚基在临床前模型中促进乳腺癌发展并调节对内分泌治疗的反应。
Br J Pharmacol. 2022 Jun;179(12):2906-2924. doi: 10.1111/bph.15147. Epub 2020 Aug 27.
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Regulatory γ1 subunits defy symmetry in functional modulation of BK channels.调节γ1 亚基在 BK 通道功能调节中打破了对称性。
Proc Natl Acad Sci U S A. 2018 Oct 2;115(40):9923-9928. doi: 10.1073/pnas.1804560115. Epub 2018 Sep 17.
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Determination of the Stoichiometry between α- and γ1 Subunits of the BK Channel Using LRET.利用 LRET 测定 BK 通道 α-和 γ1 亚基之间的化学计量比。
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