Acidic organelles, such as endosomes and lysosomes, store Ca²⁺ that is released in response to intracellular increases in the second messenger nicotinic acid adenine dinucleotide phosphate (NAADP). In neurons, NAADP and Ca²⁺ signaling contribute to synaptic plasticity, a process of activity-dependent long-term potentiation (LTP) [or, alternatively, long-term depression (LTD)] of synaptic strength and neuronal transmission that is critical for neuronal function and memory formation. We explored the function of and mechanisms regulating acidic Ca²⁺ store signaling in murine hippocampal neurons. We found that metabotropic glutamate receptor 1 (mGluR1) was coupled to NAADP signaling that elicited Ca²⁺ release from acidic stores. In turn, this released Ca²⁺-mediated mGluR1-dependent LTP by transiently inhibiting SK-type K⁺ channels, possibly through the activation of protein phosphatase 2A. Genetically removing two-pore channels (TPCs), which are endolysosomal-specific ion channels, switched the polarity of plasticity from LTP to LTD, indicating the importance of specific receptor store coupling and providing mechanistic insight into how mGluR1 can produce both synaptic potentiation and synaptic depression.

酸性细胞器，如内体和溶酶体，储存 Ca ²⁺ ，响应细胞内第二信使烟酸腺嘌呤二核苷酸磷酸 (NAADP) 的增加而释放。在神经元中，NAADP 和 Ca ²⁺信号传导有助于突触可塑性，突触可塑性是突触强度和神经元传递的活动依赖性长期增强 (LTP) [或长期抑制 (LTD)] 过程，对于神经元传递至关重要神经元功能和记忆形成。我们探索了调节小鼠海马神经元酸性 Ca ²⁺库信号传导的功能和机制。我们发现代谢型谷氨酸受体 1 (mGluR1) 与 NAADP 信号耦合，引发酸性储存中的 Ca ²⁺释放。反过来，这可能通过瞬时抑制 SK 型 K ⁺通道（可能是通过激活蛋白磷酸酶 2A）来释放 Ca ²⁺介导的 mGluR1 依赖性 LTP。通过基因去除双孔通道 (TPC)（内溶酶体特异性离子通道），将可塑性极性从 LTP 切换为 LTD，表明特定受体库耦合的重要性，并提供 mGluR1 如何产生突触增强和突触增强的机制见解。沮丧。