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

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 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 signal transmission and ryanodine-receptor-dependent Ca2+ release at ER-PM junctions over 20 μm 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. [Display omitted] •Periodic ER-PM junctions tile neuronal dendritic plasma membrane in rodent and fly•ER-PM junctions are populated by ER tethering and Ca2+ release and influx machinery•ER-PM junctions act as sites for local activation of CaMKII•Local spine activation drives Ca2+ release from RyRs at ER-PM junctions over 20 μm In neuronal dendrites of both rodents and flies, there are regularly spaced contact sites between the endoplasmic reticulum (ER) and plasma membrane, which function as hubs for regulating Ca2+ homeostasis and facilitate long-range transmission of signals along the length of the dendrite. The ladder-like patterning of the neuronal ER and its plasma membrane junctions resembles that of the sarcoplasmic reticulum-plasma membrane junctions in muscles.