Benedetti Lorena, Fan Ruolin, Weigel Aubrey V, Moore Andrew S, Houlihan Patrick R, Kittisopikul Mark, Park Grace, Petruncio Alyson, Hubbard Philip M, Pang Song, Xu C Shan, Hess Harald F, Saalfeld Stephan, Rangaraju Vidhya, Clapham David E, De Camilli Pietro, Ryan Timothy A, Lippincott-Schwartz Jennifer
HHMI Janelia Research Campus, Ashburn, VA 20147, USA.
Max Planck Florida Institute for Neuroscience, Jupiter, FL 33458, USA.
Cell. 2025 Jan 23;188(2):484-500.e22. doi: 10.1016/j.cell.2024.11.029. Epub 2024 Dec 20.
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 channels and ER Ca-release channels (ryanodine receptors), ER-PM junctions are hubs for ER-PM crosstalk, fine-tuning of Ca homeostasis, and local activation of the Ca/calmodulin-dependent protein kinase II. Local spine stimulation activates the Ca modulatory machinery, facilitating signal transmission and ryanodine-receptor-dependent Ca release at ER-PM junctions over 20 μm away. Thus, interconnected ER-PM junctions support signal propagation and Ca 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.
神经元树突必须将突触输入信号远距离传递，但活动诱发的细胞内信号在宏观距离上传播的机制仍不清楚。在这里，我们发现了一个由内质网-质膜（ER-PM）连接构成的系统，这些连接以约1微米的间隔平铺在树突的质膜上，并由呈梯状排列的内质网小管网络相互连接。ER-PM连接富含连接蛋白连接的质膜电压门控钙通道和内质网钙释放通道（兰尼碱受体），是内质网与质膜相互作用、精细调节钙稳态以及钙/钙调蛋白依赖性蛋白激酶II局部激活的枢纽。局部树突棘刺激激活钙调节机制，促进信号传递以及在20微米外的ER-PM连接处依赖兰尼碱受体的钙释放。因此，相互连接的ER-PM连接支持信号传播以及从树突棘相邻内质网释放钙。这种亚细胞结构改变局部和远距离膜近端生物化学的能力可能有助于树突计算。
