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亚型选择性的 K2 通道正变构依赖于 HA/ HB 螺旋。

Subtype-selective positive modulation of K 2 channels depends on the HA/HB helices.

机构信息

Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, California, USA.

Department of Pharmaceutical Sciences, Northeastern University School of Pharmacy, Boston, Massachusetts, USA.

出版信息

Br J Pharmacol. 2022 Feb;179(3):460-472. doi: 10.1111/bph.15676. Epub 2021 Oct 1.

DOI:10.1111/bph.15676
PMID:34458981
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8799485/
Abstract

BACKGROUND AND PURPOSE

In the activated state of small-conductance Ca -activated potassium (K 2) channels, calmodulin interacts with the HA/HB helices and the S4-S5 linker. CyPPA potentiates K 2.2a and K 2.3 channel activity but not the K 2.1 and K 3.1 subtypes.

EXPERIMENTAL APPROACH

Site-directed mutagenesis, patch-clamp recordings and in silico modelling were utilised to explore the structural determinants for the subtype-selective modulation of K 2 channels by CyPPA.

KEY RESULTS

Mutating residues in the HA (V420) and HB (K467) helices of K 2.2a channels to their equivalent residues in K 3.1 channels diminished the potency of CyPPA. CyPPA elicited prominent responses on mutant K 3.1 channels with an arginine residue in the HB helix substituted for its equivalent lysine residue in the K 2.2a channels (R355K). K 2.1 channels harbouring a three-amino-acid insertion upstream of the cognate R438 residues in the HB helix showed no response to CyPPA, whereas the deletion mutant (K 2.1_ΔA434/Q435/K436) became sensitive to CyPPA. In molecular dynamics simulations, CyPPA docked between calmodulin C-lobe and the HA/HB helices widens the cytoplasmic gate of K 2.2a channels.

CONCLUSION AND IMPLICATIONS

Selectivity of CyPPA among K 2 and K 3.1 channel subtypes relies on the HA/HB helices.

摘要

背景与目的

在小电导钙激活钾（K 2 ）通道的激活状态下，钙调蛋白与 HA/HB 螺旋和 S4-S5 连接子相互作用。CyPPA 增强 K 2.2a 和 K 2.3 通道的活性，但不增强 K 2.1 和 K 3.1 亚型。

实验方法

利用定点突变、膜片钳记录和计算机建模来探讨 CyPPA 对 K 2 通道亚型选择性调节的结构决定因素。

主要结果

将 K 2.2a 通道的 HA（V420）和 HB（K467）螺旋中的残基突变为 K 3.1 通道中的等效残基，降低了 CyPPA 的效力。CyPPA 在突变的 K 3.1 通道上引起明显的反应，其 HB 螺旋中的精氨酸取代了 K 2.2a 通道中相应的赖氨酸（R355K）。在 HB 螺旋中，K 2.1 通道上游的三个氨基酸插入使 R438 残基失去了对 CyPPA 的反应，而缺失突变体（K 2.1_ΔA434/Q435/K436）对 CyPPA 变得敏感。在分子动力学模拟中，CyPPA 在钙调蛋白 C 结构域和 HA/HB 螺旋之间结合，使 K 2.2a 通道的细胞质门变宽。

结论和意义

CyPPA 在 K 2 和 K 3.1 通道亚型之间的选择性依赖于 HA/HB 螺旋。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8c6/8799485/122a5f5753e0/nihms-1738338-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8c6/8799485/930d86706466/nihms-1738338-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8c6/8799485/2add08800d25/nihms-1738338-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8c6/8799485/4c8c3b3f7096/nihms-1738338-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8c6/8799485/de4b47175059/nihms-1738338-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8c6/8799485/2d42442380b5/nihms-1738338-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8c6/8799485/122a5f5753e0/nihms-1738338-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8c6/8799485/930d86706466/nihms-1738338-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8c6/8799485/2add08800d25/nihms-1738338-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8c6/8799485/4c8c3b3f7096/nihms-1738338-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8c6/8799485/de4b47175059/nihms-1738338-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8c6/8799485/2d42442380b5/nihms-1738338-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8c6/8799485/122a5f5753e0/nihms-1738338-f0006.jpg

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