Neuronal Ca²⁺ signals are fundamental for synaptic transmission and activity-dependent changes in gene expression. Voltage-gated Ca²⁺ channels and N-methyl-d-aspartate receptors play major roles in mediating external Ca²⁺ entry during action potential firing and glutamatergic activity. Additionally, the inositol-1,4,5-trisphosphate receptor (IP₃R) and the ryanodine receptor (RyR) channels expressed in the endoplasmic reticulum (ER) also contribute to the generation of Ca²⁺ signals in response to neuronal activity. The ER forms a network that pervades the entire neuronal volume, allowing intracellular Ca²⁺ release in dendrites, soma and presynaptic boutons. Despite its unique morphological features, the contributions of ER structure and of ER-shaping proteins such as atlastin - an ER enriched GTPase that mediates homotypic ER tubule fusion - to the generation of Ca²⁺ signals in dendrites remains unreported. Here, we investigated the contribution of RyR-mediated Ca²⁺ release to IP₃-generated Ca²⁺ signals in dendrites of cultured hippocampal neurons. We also employed GTPase activity-deficient atlastin-2 (ATL2) mutants to evaluate the potential role of atlastin on Ca²⁺ signaling and ER-resident Ca²⁺ channel distribution. We found that pharmacological suppression of RyR channel activity increased the rising time and reduced the magnitude and propagation of IP₃-induced Ca²⁺ signals. Additionally, ATL2 mutants induced specific ER morphological alterations, delayed the onset and increased the rising time of IP₃-evoked Ca²⁺ signals, and caused RyR2 and IP₃R1 aggregation and RyR2 redistribution. These results indicate that both RyR and ATL2 activity regulate IP₃-induced Ca²⁺ signal dynamics through RyR-mediated Ca²⁺-induced Ca²⁺ release, ER shaping and RyR2 distribution.

神经元 Ca ²⁺信号是基因表达中突触传递和活动依赖性变化的基础。电压门控的Ca ²⁺通道和N-甲基d天冬氨酸受体介导外部CA扮演着重要的角色²⁺期间动作电位发放和谷氨酸活动条目。此外，内质网 (ER) 中表达的肌醇 1,4,5-三磷酸受体 (IP ₃ R) 和兰尼碱受体 (RyR) 通道也有助于产生响应神经元活动的 Ca ²⁺信号。ER 形成一个遍布整个神经元体积的网络，允许细胞内 Ca ²⁺在树突、胞体和突触前按钮中释放。尽管具有独特的形态特征，但 ER 结构和 ER 成形蛋白（例如 atlastin（一种富含 ER 的 GTPase，介导同型 ER 小管融合）对树突中 Ca ²⁺信号产生的贡献仍未报道。在这里，我们研究了 RyR 介导的 Ca ²⁺释放对培养的海马神经元树突中IP ₃产生的 Ca ²⁺信号的贡献。我们还使用 GTPase 活性缺陷 atlastin-2 (ATL2) 突变体来评估 atlastin 对 Ca ²⁺信号传导和内质网驻留 Ca ²⁺的潜在作用渠道分布。我们发现 RyR 通道活性的药理学抑制增加了上升时间并减少了 IP ₃诱导的 Ca ²⁺信号的幅度和传播。此外，ATL2 突变体诱导特定的 ER 形态改变，延迟发作并增加 IP ₃诱发的 Ca ²⁺信号的上升时间，并导致 RyR2 和 IP ₃ R1 聚集和 RyR2 重新分布。这些结果表明，RyR 和 ATL2 活性均通过 RyR 介导的 Ca ²⁺诱导的 Ca ²⁺释放、ER 成形和 RyR2 分布来调节 IP ₃诱导的 Ca ²⁺信号动力学。