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bioRxiv · 10.1101/2024.05.27.596121

Periodic ER-plasma membrane junctions support long-range Ca2+ signal integration in dendrites

Benedetti, L.·Fan, R.·Weigel, A. V.·Moore, A. S.·Houlihan, P. R.·Kittisopikul, M.·Park, G.·Petruncio, A.·Hubbard, P. M.·Pang, S.·Xu, C. S.·Hess, H.·Saalfeld, S.·Rangaraju, V.·Clapham, D. E.·De Camilli, P.·Ryan, T. A.·Lippincott-Schwartz, J.
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Abstract

Neuronal dendrites must relay synaptic inputs over long distances, but the mechanisms by which activity-evoked intracellular signals propagate over macroscopic distances remain unclear. Here, we discovered a system of periodically arranged endoplasmic reticulum-plasma membrane (ER-PM) junctions tiling the plasma membrane of dendrites at [~]1 m intervals, interlinked by a meshwork of ER tubules patterned in a ladder-like array. Populated with Junctophilin-linked plasma membrane voltage-gated Ca2+ channels and ER Ca2+-release channels (ryanodine receptors), ER-PM junctions are hubs for ER-PM crosstalk, fine-tuning of Ca2+ homeostasis, and local activation of the Ca2+/calmodulin-dependent protein kinase II. Local spine stimulation activates the Ca2+ modulatory machinery facilitating voltage-independent signal transmission and ryanodine receptor-dependent Ca2+ release at ER-PM junctions over 20 m away. Thus, interconnected ER-PM junctions support signal propagation and Ca2+ release from the spine-adjacent ER. The capacity of this subcellular architecture to modify both local and distant membrane-proximal biochemistry potentially contributes to dendritic computations. HighlightsO_LIPeriodic ER-PM junctions tile neuronal dendritic plasma membrane in rodent and fly. C_LIO_LIER-PM junctions are populated by ER tethering and Ca2+ release and influx machinery. C_LIO_LIER-PM junctions act as sites for local activation of CaMKII. C_LIO_LILocal spine activation drives Ca2+ release from RyRs at ER-PM junctions over 20 m. C_LI

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Benedetti, L., Fan, R., Weigel, A. V., Moore, A. S., Houlihan, P. R., Kittisopikul, M., Park, G., Petruncio, A., Hubbard, P. M., Pang, S., Xu, C. S., Hess, H., Saalfeld, S., Rangaraju, V., Clapham, D. E., De Camilli, P., Ryan, T. A., Lippincott-Schwartz, J.. 2024-05-31. Periodic ER-plasma membrane junctions support long-range Ca2+ signal integration in dendrites. https://doi.org/10.1101/2024.05.27.596121

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