Membrane contact sites, or junctions, between the cortical endoplasmic reticulum (cER) and the plasma membrane are of great importance for signal transduction. In neurons, ER projections near the plasma membrane are found next to clusters of the major delayed-rectifier K+ channel protein Kv2.1. Here (p. ), Michael Tamkun and colleagues use total internal reflection microscopy and electron microscopy to investigate the mechanism of ER–plasma-membrane junction formation, maintenance and function in primary rat hippocampal neurons and HEK293 cells. They found that expression of Kv2.1 induced cER remodelling and formation of ER–plasma-membrane junctions, with the two membranes positioned less than 20 nm away from one another. To support their hypothesis that Kv2.1 clustering is required for the formation of ER–plasma-membrane junctions, the authors demonstrated that inhibition of clustering through the use of Kv2.1 phosphorylation point mutants prevented remodelling of the cER and formation of ER–plasma-membrane junctions. Finally, the authors found that Cav1.2 Ca2+ channels and the ER-resident STIM1 protein localised to the ER–plasma-membrane junctions. Interestingly, STIM1 responded to a decrease in ER Ca2+ levels by recruiting the plasma-membrane-resident Ca2+ channel ORAI1 to the Kv2.1 clusters. This work demonstrates that Kv2.1 clusters have a direct role in the formation and maintenance of ER–plasma-membrane junctions in neurons, which function as sites of Ca2+ signalling regulation.
