Structural Basis for the Subtype-Selectivity of K_Ca2.2 Channel Activators

Authors

Young-Woo Nam, Chapman UniversityFollow
Alena Ramanishka, Chapman University
Yang Xu, Stanford University
Rose Marie Haynes Yasuda, Oregon Health & Science University
Joshua A. Nasburg, University of California, Davis
Dohyun Im, Kyoto University
Meng Cui, Northeastern University
K. George Chandy, Nanyang Technological University
Heike Wulff, University of California, Davis
Miao Zhang, Chapman UniversityFollow

Document Type

Article

Publication Date

1-8-2026

Abstract

Small-conductance (K_Ca2.2) and intermediate-conductance (K_Ca3.1) Ca²⁺-activated K⁺ channels are gated by a Ca²⁺-calmodulin dependent mechanism. NS309 potentiates the activity of both K_Ca2.2 and K_Ca3.1, while rimtuzalcap selectively activates K_Ca2.2. Rimtuzalcap has been used in clinical trials for the treatment of spinocerebellar ataxia and essential tremor. We report cryo-electron microscopy structures of NS309-bound K_Ca2.2 and K_Ca3.1, in addition to structures of rimtuzalcap-bound K_Ca2.2 and mutant K_Ca3.1_R355K. The different conformations of calmodulin and the cytoplasmic HC helices in the two channels underlie the subtype-selectivity of rimtuzalcap for K_Ca2.2. NS309 binds to pre-existing pockets in both channels, while the bulkier rimtuzalcap binds in an induced-fit pocket in K_Ca2.2 requiring conformational changes. In K_Ca2.2, calmodulin’s N-lobes are sufficiently far apart to enable conformational changes to accommodate either NS309 or rimtuzalcap. In K_Ca3.1, calmodulin’s N-lobes are closer to each other and constrained by K_Ca3.1’s HC helices, which allows binding of NS309 but not rimtuzalcap. Replacement of arginine-355 in K_Ca3.1’s HB helix with lysine (K_Ca3.1_R355K) allows the binding of rimtuzalcap and renders the mutant channel sensitive to rimtuzalcap. These structures provide a framework for structure-based drug design targeting K_Ca2.2 channels.

Comments

This article was originally published in Nature Communications, volume 17, in 2026. https://doi.org/10.1038/s41467-025-67232-3

Recommended Citation

Nam, YW., Ramanishka, A., Xu, Y. et al. Structural basis for the subtype-selectivity of KCa2.2 channel activators. Nat Commun 17, 531 (2026). https://doi.org/10.1038/s41467-025-67232-3

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