Dynamic L-type CaV1.2 channel trafficking facilitates CaV1.2 clustering and cooperative gating

L-type CaV1.2 channels are key regulators of gene expression, cell excitability and muscle contraction. CaV1.2 channels organize in clusters throughout the plasma membrane. This channel organization has been suggested to contribute to the concerted activation of adjacent CaV1.2 channels (e.g. cooper...

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Published in:Biochimica et biophysica acta. Molecular cell research 2018-09, Vol.1865 (9), p.1341-1355
Main Authors: Ghosh, Debapriya, Nieves-Cintrón, Madeline, Tajada, Sendoa, Brust-Mascher, Ingrid, Horne, Mary C., Hell, Johannes W., Dixon, Rose E., Santana, Luis F., Navedo, Manuel F.
Format: Article
Language:English
Subjects:
Coupled gating
In vivo imaging
Ion channels
Vesicles
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Summary:L-type CaV1.2 channels are key regulators of gene expression, cell excitability and muscle contraction. CaV1.2 channels organize in clusters throughout the plasma membrane. This channel organization has been suggested to contribute to the concerted activation of adjacent CaV1.2 channels (e.g. cooperative gating). Here, we tested the hypothesis that dynamic intracellular and perimembrane trafficking of CaV1.2 channels is critical for formation and dissolution of functional channel clusters mediating cooperative gating. We found that CaV1.2 moves in vesicular structures of circular and tubular shape with diverse intracellular and submembrane trafficking patterns. Both microtubules and actin filaments are required for dynamic movement of CaV1.2 vesicles. These vesicles undergo constitutive homotypic fusion and fission events that sustain CaV1.2 clustering, channel activity and cooperative gating. Our study suggests that CaV1.2 clusters and activity can be modulated by diverse and unique intracellular and perimembrane vesicular dynamics to fine-tune Ca2+ signals. [Display omitted] •Live-cell imaging revealed dynamic perimembrane and intracellular CaV1.2 trafficking.•This occurs in vesicular compartments of circular and tubular shape.•CaV1.2 vesicles exhibit distinct perimembrane behaviors requiring intact cytoskeleton.•Homotypic fusion of CaV1.2 vesicles results in increased CaV1.2 cluster density.•CaV1.2 vesicular trafficking sustains CaV1.2 clustering, activity, and cooperative gating.
ISSN:0167-4889
1879-2596
DOI:10.1016/j.bbamcr.2018.06.013