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Calcium induced N-terminal gating and pore collapse in connexin-46/50 gap junctions
Jonathan A Flores1,2,3, Susan E O'Neill1,2, Joshua M Jarodsky1,2
1Department of Chemical Physiology and Biochemistry, Oregon Health and Science University, Portland, OR 97239, USA.
Biorxiv : the Preprint Server for Biology
|February 24, 2025
Summary
Calcium ions (Ca2+) uncouple gap junctions during ischemia to protect cells. New cryo-EM structures reveal how Ca2+ binding and N-terminal domain remodeling control connexin-46/50 channel gating, explaining cell communication regulation.
Area of Science:
- Cellular Biology
- Biophysics
- Structural Biology
Background:
- Gap junctions mediate essential electrical and metabolic coupling for tissue function.
- Ischemic conditions, such as heart attack or stroke, trigger elevated intracellular calcium (Ca2+) levels.
- This calcium increase leads to the uncoupling of gap junctions, protecting healthy cells from damage.
Purpose of the Study:
- To elucidate the Ca2+-induced gating mechanism of native connexin-46/50 (Cx46/50) gap junctions.
- To provide detailed structural insights into how Ca2+ regulates cell-to-cell communication.
Main Methods:
- Single-particle cryo-electron microscopy (cryo-EM) was employed.
- High-resolution structures of Cx46/50 gap junctions were resolved.
Main Results:
- Ca2+ binding sites were identified within the channel pore, altering the permeation pathway.
- N-terminal domain remodeling was observed, leading to diverse occluded and gated states.
- Subunit rearrangements resulted in pore collapse, with N-terminal domains causing steric blockade, supporting an "iris model" of gating.
Conclusions:
- The study provides mechanistic insights into Ca2+ signaling regulating gap junction uncoupling.
- Findings unify and expand upon previous gap junction gating models.
- The results have broader implications for understanding cellular stress responses and tissue protection mechanisms.
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