Mechanisms of intracellular pH gating and local anesthetic inhibition of the two-pore domain K⁺ channel TASK-2.
6 affiliations
- 1Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, CA 94720.
- 2Department of Neuroscience, University of California Berkeley, Berkeley, CA 94720.
- 3Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA 94720.
- 4Biophysics Graduate Program, University of California, Berkeley, CA 94720.
- 5Materials and Structural Analysis, Thermo Fisher Scientific, Eindhoven 5651 GG, The Netherlands.
- 6California Institute for Quantitative Biosciences, University of California, Berkeley, CA 94720.
Abstract
TWIK-related acid-sensitive K+ channel 2 (TASK-2) is a pH sensing two-pore K⁺ (K2P) channel that regulates respiration in brainstem neurons and systemic pH homeostasis in kidney. Despite its physiological importance and implication in disease, the molecular basis for intracellular gating and pharmacological inhibition of TASK-2 is incompletely understood. Here, we combine cryo-EM and single-channel electrophysiology to resolve the mechanisms of TASK-2 gating by intracellular protons and inhibition by the anesthetic bupivacaine. We show protonation of intracellular lysines triggers a unique stacked gating mechanism distinct from other K⁺ channels. Inner helices unwind and domain swap to form a β-zipper, which we call a Z-gate, that seals the cytoplasmic channel entrance. These conformational changes open lateral fenestrations to the membrane that permit lipids to invade the channel cavity and block the pore. Furthermore, we find bupivacaine inhibits the channel by competing with lipids in the cavity site in a state-dependent manner. These results define a paradigm for intracellular gating of K2Ps and provide a structural foundation for designing more potent and selective channel modulators.
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BibTeX
@article{docter2026mechanisms,
title = {{Mechanisms of intracellular pH gating and local anesthetic inhibition of the two-pore domain K⁺ channel TASK-2.}},
author = {Trevor Docter and Ben Sorum and Baobin Li and Robert A Rietmeijer and Annan S I Cook and Abhay Kotecha and Stephen G Brohawn},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2026},
month = oct,
doi = {10.1073/pnas.2604873123},
url = {https://europepmc.org/article/MED/42848420},
note = {CC BY},
}
RIS
TY - JOUR
TI - Mechanisms of intracellular pH gating and local anesthetic inhibition of the two-pore domain K⁺ channel TASK-2.
AU - Trevor Docter
AU - Ben Sorum
AU - Baobin Li
AU - Robert A Rietmeijer
AU - Annan S I Cook
AU - Abhay Kotecha
AU - Stephen G Brohawn
PY - 2026
DA - 2026/10/08
JO - Proceedings of the National Academy of Sciences of the United States of America
DO - 10.1073/pnas.2604873123
UR - https://europepmc.org/article/MED/42848420
AB - TWIK-related acid-sensitive K+ channel 2 (TASK-2) is a pH sensing two-pore K⁺ (K2P) channel that regulates respiration in brainstem neurons and systemic pH homeostasis in kidney. Despite its physiological importance and implication in disease, the molecular basis for intracellular gating and pharmacological inhibition of TASK-2 is incompletely understood. Here, we combine cryo-EM and single-channel electrophysiology to resolve the mechanisms of TASK-2 gating by intracellular protons and inhibition by the anesthetic bupivacaine. We show protonation of intracellular lysines triggers a unique stacked gating mechanism distinct from other K⁺ channels. Inner helices unwind and domain swap to form a β-zipper, which we call a Z-gate, that seals the cytoplasmic channel entrance. These conformational changes open lateral fenestrations to the membrane that permit lipids to invade the channel cavity and block the pore. Furthermore, we find bupivacaine inhibits the channel by competing with lipids in the cavity site in a state-dependent manner. These results define a paradigm for intracellular gating of K2Ps and provide a structural foundation for designing more potent and selective channel modulators.
SN - 0027-8424
SN - 1091-6490
ER -