Atomistic mechanisms of the regulation of small-conductance Ca <sup>2+</sup> -activated K <sup>+</sup> channel (SK2) by PIP2

Small-conductance Ca<sup>2+</sup>-activated K<sup>+</sup> channels (SK, K<sub>Ca</sub>2) are gated solely by intracellular microdomain Ca<sup>2+</sup>. The channel has emerged as a therapeutic target for cardiac arrhythmias. Calmodulin (CaM) interacts with the CaM binding domain (CaMBD) of the SK channels, serving as the obligatory Ca<sup>2+</sup> sensor to gate the channels. In heterologous expression systems, phosphatidylinositol 4,5-bisphosphate (PIP2) coordinates with CaM in regulating SK channels. However, the roles and mechanisms of PIP2 in regulating SK channels in cardiomyocytes remain unknown. Here, optogenetics, magnetic nanoparticles, combined with <i>Rosetta</i> structural modeling, and molecular dynamics (MD) simulations revealed the atomistic mechanisms of how PIP2 works in concert with Ca<sup>2+</sup>-CaM in the SK channel activation. Our computational study affords evidence for the critical role of the amino acid residue R395 in the S6 transmembrane segment, which is localized in propinquity to the intracellular hydrophobic gate. This residue forms a salt bridge with residue E398 in the S6 transmembrane segment from the adjacent subunit. Both R395 and E398 are conserved in all known isoforms of SK channels. Our findings suggest that the binding of PIP2 to R395 residue disrupts the R395:E398 salt bridge, increasing the flexibility of the transmembrane segment S6 and the activation of the channel. Importantly, our findings serve as a platform for testing of structural-based drug designs for therapeutic inhibitors and activators of the SK channel family. The study is timely since inhibitors of SK channels are currently in clinical trials to treat atrial arrhythmias.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2024-09-17
DOI
https://doi.org/10.1073/pnas.2318900121
Citations
11
Primary Topic
Ion channel regulation and function
Type
article
Field-Weighted Citation Impact
2.57

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article

Atomistic mechanisms of the regulation of small-conductance Ca 2+ -activated K + channel (SK2) by PIP2

Diego López Mateos, Kyle C. Rouen, Pauline Trinh, Yanxiao Han et al.
11 citations
Proceedings of the National Academy of Sciences
Ion channel regulation and function
2.57
article

Atomistic mechanisms of the regulation of small-conductance Ca 2+ -activated K + channel (SK2) by PIP2

Diego López Mateos, Kyle C. Rouen, Pauline Trinh, Yanxiao Han, Igor Vorobyov, Nipavan Chiamvimonvat, Ye Chen‐Izu, Lu Ren, Khoa Ngo, Phung Ngoc Thai, Zhong Jian, Yang Zheng, Ryan L. Woltz, Eamonn J. Dickson, Vladimir M. Yarov-Yarovoy, B. Harris, Xiao-Dong Zhang, Ebenezer N. Yamoah, Woori Choi
article en
11 citations

Abstract

Small-conductance Ca<sup>2+</sup>-activated K<sup>+</sup> channels (SK, K<sub>Ca</sub>2) are gated solely by intracellular microdomain Ca<sup>2+</sup>. The channel has emerged as a therapeutic target for cardiac arrhythmias. Calmodulin (CaM) interacts with the CaM binding domain (CaMBD) of the SK channels, serving as the obligatory Ca<sup>2+</sup> sensor to gate the channels. In heterologous expression systems, phosphatidylinositol 4,5-bisphosphate (PIP2) coordinates with CaM in regulating SK channels. However, the roles and mechanisms of PIP2 in regulating SK channels in cardiomyocytes remain unknown. Here, optogenetics, magnetic nanoparticles, combined with <i>Rosetta</i> structural modeling, and molecular dynamics (MD) simulations revealed the atomistic mechanisms of how PIP2 works in concert with Ca<sup>2+</sup>-CaM in the SK channel activation. Our computational study affords evidence for the critical role of the amino acid residue R395 in the S6 transmembrane segment, which is localized in propinquity to the intracellular hydrophobic gate. This residue forms a salt bridge with residue E398 in the S6 transmembrane segment from the adjacent subunit. Both R395 and E398 are conserved in all known isoforms of SK channels. Our findings suggest that the binding of PIP2 to R395 residue disrupts the R395:E398 salt bridge, increasing the flexibility of the transmembrane segment S6 and the activation of the channel. Importantly, our findings serve as a platform for testing of structural-based drug designs for therapeutic inhibitors and activators of the SK channel family. The study is timely since inhibitors of SK channels are currently in clinical trials to treat atrial arrhythmias.

Proceedings of the National Academy of SciencesVol. 121(39)
University of Arizona (US), Cardiovascular Institute of the South (US), VA Northern California Health Care System (US), University of California, Davis (US), Stanford University (US)
U.S. Department of Veterans Affairs, American Heart Association, Heart Rhythm Society, National Institutes of Health, University of California, Davis, National Institute on Aging, National Heart, Lung, and Blood Institute, National Institute on Deafness and Other Communication Disorders, National Institute of General Medical Sciences, Stanford Cardiovascular Institute, School of Medicine, Stanford University, Common Fund
Openalex Percentile: Top 10%
Ion channel regulation and function
2.57
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