Auxiliary BKβ4 subunits promote nanoscale coupling between BK and voltage-gated calcium channels
- 1Department of Basic Medical Sciences-Physiology, Universidad de La Laguna, La Laguna 38071, Spain
- 2Institute of Biomedical Technologies, Universidad de La Laguna, La Laguna 38200, Spain
- 3Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna, La Laguna 38071, Spain
Abstract
Intracellular Ca2+ signals are essential for many cellular processes but must be tightly regulated to ensure precise spatial and temporal control. The large conductance calcium- and voltage-activated K+ channel (BK) integrates intracellular Ca2+ signaling and membrane depolarization to generate hyperpolarizing K+ currents that regulate membrane excitability. In many cell types, BK channels achieve rapid activation through functional coupling with voltage-gated calcium (CaV) channels that provide localized Ca2+ signals. However, the mechanisms that regulate the nanoscale organization of BK+CaV channel complexes remain poorly understood. Here we investigated whether the BK auxiliary subunit β4 (BKβ4), which is widely expressed throughout the brain and modulates BK gating properties, influences the spatial organization and functional coupling of BK and CaV channels. Using proximity ligation assays, electrophysiology, and superresolution stochastic optical reconstruction microscopy, we show that BKβ4 promotes BK+CaV nanodomain organization by increasing channel clustering and altering their spatial proximity at the plasma membrane. These structural changes enhance functional coupling between Ca2+ influx and BK channel activation. Notably, the effects of BKβ4 on nanodomain organization and coupling depend on the CaV subtype involved. Together, our findings reveal that the BKβ4 auxiliary subunit regulates the nanoscale architecture of BK+CaV channel complexes and thereby modulates their functional interaction.
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BibTeX
@article{kshatri2026auxiliary,
title = {{Auxiliary BKβ4 subunits promote nanoscale coupling between BK and voltage-gated calcium channels}},
author = {Aravind Kshatri and Luis O. Romero and Alberto J. Gonzalez-Hernandez and Alejandro Cerrada and Belinda Rivero-Pérez and David Bartolomé-Martín and Teresa Giraldez},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2026},
month = oct,
doi = {10.1073/pnas.2609903123},
url = {https://doi.org/10.1073/pnas.2609903123},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Auxiliary BKβ4 subunits promote nanoscale coupling between BK and voltage-gated calcium channels
AU - Aravind Kshatri
AU - Luis O. Romero
AU - Alberto J. Gonzalez-Hernandez
AU - Alejandro Cerrada
AU - Belinda Rivero-Pérez
AU - David Bartolomé-Martín
AU - Teresa Giraldez
PY - 2026
DA - 2026/10/28
JO - Proceedings of the National Academy of Sciences of the United States of America
DO - 10.1073/pnas.2609903123
UR - https://doi.org/10.1073/pnas.2609903123
AB - Intracellular Ca2+ signals are essential for many cellular processes but must be tightly regulated to ensure precise spatial and temporal control. The large conductance calcium- and voltage-activated K+ channel (BK) integrates intracellular Ca2+ signaling and membrane depolarization to generate hyperpolarizing K+ currents that regulate membrane excitability. In many cell types, BK channels achieve rapid activation through functional coupling with voltage-gated calcium (CaV) channels that provide localized Ca2+ signals. However, the mechanisms that regulate the nanoscale organization of BK+CaV channel complexes remain poorly understood. Here we investigated whether the BK auxiliary subunit β4 (BKβ4), which is widely expressed throughout the brain and modulates BK gating properties, influences the spatial organization and functional coupling of BK and CaV channels. Using proximity ligation assays, electrophysiology, and superresolution stochastic optical reconstruction microscopy, we show that BKβ4 promotes BK+CaV nanodomain organization by increasing channel clustering and altering their spatial proximity at the plasma membrane. These structural changes enhance functional coupling between Ca2+ influx and BK channel activation. Notably, the effects of BKβ4 on nanodomain organization and coupling depend on the CaV subtype involved. Together, our findings reveal that the BKβ4 auxiliary subunit regulates the nanoscale architecture of BK+CaV channel complexes and thereby modulates their functional interaction.
SN - 0027-8424
SN - 1091-6490
ER -