Summary 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 μm intervals, interlinked by a meshwork of ER tubules patterned in a ladder-like array. Populated with Junctophilin-linked plasma membrane voltage-gated Ca 2+ channels and ER Ca 2+ -release channels (ryanodine receptors), ER-PM junctions are hubs for ER-PM crosstalk, fine-tuning of Ca 2+ homeostasis, and local activation of the Ca 2+ /calmodulin-dependent protein kinase II. Local spine stimulation activates the Ca 2+ modulatory machinery facilitating voltage-independent signal transmission and ryanodine receptor-dependent Ca 2+ release at ER-PM junctions over 20 μm away. Thus, interconnected ER-PM junctions support signal propagation and Ca 2+ 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. Highlights Periodic ER-PM junctions tile neuronal dendritic plasma membrane in rodent and fly. ER-PM junctions are populated by ER tethering and Ca 2+ release and influx machinery. ER-PM junctions act as sites for local activation of CaMKII. Local spine activation drives Ca 2+ release from RyRs at ER-PM junctions over 20 μm.

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