TRPML1 (transient receptor potential mucolipin 1) is a Ca²⁺-permeable, nonselective cation channel localized to the membranes of endosomes and lysosomes and is not present or functional on the plasma membrane. Ca²⁺ released from endosomes and lysosomes into the cytosol through TRPML1 channels is vital for trafficking, acidification, and other basic functions of these organelles. Here, we investigated the function of TRPML1 channels in fully differentiated contractile vascular smooth muscle cells (SMCs). In live-cell confocal imaging studies, we found that most endosomes and lysosomes in freshly isolated SMCs from cerebral arteries were essentially immobile. Using nanoscale super-resolution microscopy, we found that TRPML1 channels present in late endosomes and lysosomes formed stable complexes with type 2 ryanodine receptors (RyR2) on the sarcoplasmic reticulum (SR). Spontaneous Ca²⁺ signals resulting from the release of SR Ca²⁺ through RyR2s (“Ca²⁺ sparks”) and corresponding Ca²⁺-activated K⁺ channel activity are critically important for balancing vasoconstriction. We found that these signals were essentially absent in SMCs from TRPML1-knockout (Mcoln1^−/−) mice. Using ex vivo pressure myography, we found that loss of this critical signaling cascade exaggerated the vasoconstrictor responses of cerebral and mesenteric resistance arteries. In vivo radiotelemetry studies showed that Mcoln1^−/− mice were spontaneously hypertensive. We conclude that TRPML1 is crucial for the initiation of Ca²⁺ sparks in SMCs and the regulation of vascular contractility and blood pressure.

TRPML1（瞬时受体电位粘蛋白 1）是一种 Ca ²⁺可渗透的非选择性阳离子通道，位于内体和溶酶体的膜上，在质膜上不存在或不发挥功能。钙²⁺通过 TRPML1 通道从内体和溶酶体释放到胞质溶胶中的蛋白质对这些细胞器的运输、酸化和其他基本功能至关重要。在这里，我们研究了 TRPML1 通道在完全分化的收缩血管平滑肌细胞 (SMC) 中的功能。在活细胞共聚焦成像研究中，我们发现从脑动脉新鲜分离的 SMC 中的大多数内体和溶酶体基本上是不动的。使用纳米级超分辨率显微镜，我们发现晚期内体和溶酶体中存在的 TRPML1 通道与肌浆网 (SR) 上的 2 型兰尼碱受体 (RyR2) 形成稳定的复合物。自发的Ca ²⁺信号从SR Ca的释放导致²⁺通过RyR2s（“钙²⁺sparks”）和相应的 Ca ²⁺激活的 K ⁺通道活性对于平衡血管收缩至关重要。我们发现这些信号在来自 TRPML1 基因敲除 ( Mcoln1 ^-/- ) 小鼠的SMC 中基本不存在。使用离体压力肌电图，我们发现这种关键信号级联的丧失会夸大脑和肠系膜阻力动脉的血管收缩反应。体内无线电遥测研究表明Mcoln1 ^-/-小鼠是自发性高血压。我们得出结论，TRPML1 对于SMC中 Ca ²⁺火花的启动以及血管收缩力和血压的调节至关重要。