Calcium induced N-terminal gating and pore collapse in connexin-46/50 gap junctions.
6 affiliations
- 1Department of Chemical Physiology and Biochemistry, Oregon Health and Science University, Portland, OR, USA
- 2Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
- 3Vollum Institute, Oregon Health and Science University, Portland, OR, USA
- 4Institute of Neurophysiology, Hannover Medical School, Hannover, Germany
- 5Department of Chemical Physiology and Biochemistry, Oregon Health and Science University, Portland, OR, USA. [email protected]
- 6Vollum Institute, Oregon Health and Science University, Portland, OR, USA. [email protected]
Abstract
Gap junctions facilitate electrical and metabolic coupling essential for tissue function. Under ischemic conditions (e.g., heart attack or stroke), elevated intracellular calcium (Ca²⁺) uncouples these communication pathways to limit the spread of cytotoxic signals, yet the structural basis of this protective response remains unclear. Here, using single-particle cryo-EM, we define the Ca²⁺-dependent gating mechanism of native connexin-46/50 (Cx46/50) gap junction channels. Ca²⁺ binding promotes an ensemble of N-terminal (NT) domain conformations spanning destabilized and fully gated states. These conformational changes are coupled to coordinated subunit rearrangements that asymmetrically collapse the pore and enable steric occlusion by the NT domains. Comparison with recently resolved low-pH gating structures reveals that distinct physiological stimuli converge on a common NT-centered gating mechanism involving coupled NT displacement and TM2 hinge motion. Long-timescale molecular dynamics simulations identify multiple Ca²⁺ interaction sites along the permeation pathway and suggest that transient inter-subunit Ca²⁺ coordination can promote NT destabilization and displacement. Together, these findings support a model in which distributed Ca²⁺ interactions reshape the energetic landscape of the channel to favor NT-mediated pore closure, unifying previous models of gap junction regulation and providing a mechanistic basis for Ca²⁺-dependent uncoupling during cellular stress.
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BibTeX
@article{flores2026calcium,
title = {{Calcium induced N-terminal gating and pore collapse in connexin-46/50 gap junctions.}},
author = {Jonathan A. Flores and Susan E. O'Neill and Joshua M. Jarodsky and Bassam G. Haddad and Steve Reichow},
journal = {Nature communications},
year = {2026},
month = sep,
doi = {10.1038/s41467-026-77891-5},
url = {https://europepmc.org/article/MED/42918775},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Calcium induced N-terminal gating and pore collapse in connexin-46/50 gap junctions.
AU - Jonathan A. Flores
AU - Susan E. O'Neill
AU - Joshua M. Jarodsky
AU - Bassam G. Haddad
AU - Steve Reichow
PY - 2026
DA - 2026/09/23
JO - Nature communications
DO - 10.1038/s41467-026-77891-5
UR - https://europepmc.org/article/MED/42918775
AB - Gap junctions facilitate electrical and metabolic coupling essential for tissue function. Under ischemic conditions (e.g., heart attack or stroke), elevated intracellular calcium (Ca²⁺) uncouples these communication pathways to limit the spread of cytotoxic signals, yet the structural basis of this protective response remains unclear. Here, using single-particle cryo-EM, we define the Ca²⁺-dependent gating mechanism of native connexin-46/50 (Cx46/50) gap junction channels. Ca²⁺ binding promotes an ensemble of N-terminal (NT) domain conformations spanning destabilized and fully gated states. These conformational changes are coupled to coordinated subunit rearrangements that asymmetrically collapse the pore and enable steric occlusion by the NT domains. Comparison with recently resolved low-pH gating structures reveals that distinct physiological stimuli converge on a common NT-centered gating mechanism involving coupled NT displacement and TM2 hinge motion. Long-timescale molecular dynamics simulations identify multiple Ca²⁺ interaction sites along the permeation pathway and suggest that transient inter-subunit Ca²⁺ coordination can promote NT destabilization and displacement. Together, these findings support a model in which distributed Ca²⁺ interactions reshape the energetic landscape of the channel to favor NT-mediated pore closure, unifying previous models of gap junction regulation and providing a mechanistic basis for Ca²⁺-dependent uncoupling during cellular stress.
SN - 2041-1723
ER -