Mobilization of calcium from intracellular stores facilitates somatodendritic dopamine release.
Mobilization of calcium from intracellular stores facilitates somatodendritic dopamine release.
复制标题
DOI：
10.1523/jneurosci.0181-09.2009
复制
发表时间：
2009-05-20
期刊：
影响因子：
--
通讯作者：
Rice ME
中科院分区：
文献类型：
--
作者：
Patel JC;Witkovsky P;Avshalumov MV;Rice ME
黑质神经元多巴胺（DA）的释放对细胞外钙离子浓度（[Ca ~（2+）]o）的依赖性有限，提示与细胞内Ca ~（2+）库有关。在这里，使用免疫细胞化学，我们证明了存在的肌质/内质网Ca 2 +-ATP酶2（SERCA 2），螯合胞质Ca 2+进入内质网（ER），以及肌醇1，4，5-三磷酸受体（IP 3Rs）和兰尼碱受体（RyRs）DA能神经元。值得注意的是，RyR聚集在质膜上，准备通过Ca 2+进入激活。利用快速扫描循环伏安法监测中脑脑片诱发的细胞外DA浓度（[DA]o），发现环匹阿尼酸（CPA）抑制SERCA可降低SNc诱发的[DA]o，表明ER Ca 2+库在体树突DA释放中发挥功能性作用。IP 3R拮抗剂2-APB也可降低诱发的[DA]o。此外，DHPG，一个激动剂的I组代谢型谷氨酸受体（mGluR 1 s，这对IP 3的生产），增加体树突DA释放，而CPCCOEt，mGluR 1拮抗剂，抑制它。释放抑制mGluR 1封锁被阻止2-APB或CPA，表明促进DA释放的内源性谷氨酸通过mGluR 1 s和IP 3R门控的Ca 2+商店。同样，咖啡因激活RyR增加[Ca 2 +]i和升高诱发的[DA]o。DA释放的增加被RyR阻断剂丹曲林和CPA阻止。重要的是，丹曲林的功效在低[Ca 2 +]o中增强，这表明在有限的Ca 2+进入的情况下维持体树突DA释放的机制。因此，mGluR 1连接的IP 3R和RyR依赖的ER Ca 2+商店促进体树突DA在SNc的释放。
Somatodendritic dopamine (DA) release in the substantia nigra pars compacta (SNc) shows a limited dependence on extracellular calcium concentration ([Ca2+]o), suggesting the involvement of intracellular Ca2+ stores. Here, using immunocytochemistry we demonstrate the presence of the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2 (SERCA2) that sequesters cytosolic Ca2+ into the endoplasmic reticulum (ER), as well as inositol 1,4,5-triphosphate receptors (IP3Rs) and ryanodine receptors (RyRs) in DAergic neurons. Notably, RyRs were clustered at the plasma membrane, poised for activation by Ca2+ entry. Using fast-scan cyclic voltammetry to monitor evoked extracellular DA concentration ([DA]o) in midbrain slices, we found that SERCA inhibition by cyclopiazonic acid (CPA) decreased evoked [DA]o in the SNc, indicating a functional role for ER Ca2+ stores in somatodendritic DA release. Implicating IP3R-dependent stores, an IP3R antagonist, 2-APB, also decreased evoked [DA]o. Moreover, DHPG, an agonist of group I metabotropic glutamate receptors (mGluR1s, which couple to IP3 production), increased somatodendritic DA release, whereas CPCCOEt, an mGluR1 antagonist, suppressed it. Release suppression by mGluR1 blockade was prevented by 2-APB or CPA, indicating facilitation of DA release by endogenous glutamate acting via mGluR1s and IP3R-gated Ca2+ stores. Similarly, activation of RyRs by caffeine increased [Ca2+]i and elevated evoked [DA]o. The increase in DA release was prevented by a RyR blocker, dantrolene, and by CPA. Importantly, the efficacy of dantrolene was enhanced in low [Ca2+]o, suggesting a mechanism for maintenance of somatodendritic DA release with limited Ca2+ entry. Thus, both mGluR1-linked IP3R- and RyR-dependent ER Ca2+ stores facilitate somatodendritic DA release in the SNc.