Inhibition of striatal dopamine release by the L-type calcium channel inhibitor isradipine co-varies with risk factors for Parkinson's
Inhibition of striatal dopamine release by the L-type calcium channel inhibitor isradipine co-varies with risk factors for Parkinson's
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L 型钙通道抑制剂伊拉地平对纹状体多巴胺释放的抑制作用与帕金森病的危险因素共同变化
DOI：
10.1101/2020.07.03.186411
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发表时间：
2020
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影响因子：
--
通讯作者：
Brimblecombe K
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作者：
Brimblecombe K
Ca2+ 通过 L 型电压门控 Ca2+ 通道 (LTCC) 进入黑质纹状体多巴胺 (DA) 神经元和轴突，分别有助于起搏器活动和 DA 释放，长期以来一直被认为与帕金森病的退化有关。黑质致密部的 DA 轴突和神经元中的 LTCC 功能比腹侧被盖区的 DA 轴突和神经元更强，但这不能用通道表达水平来解释。我们测试了这样的假设，即 LTCC 对 DA 释放的控制是由局部机制控制的，重点关注已知在 DA 神经元类型之间运作不同和/或与其不同的帕金森病易感性相关的候选生物因素，包括生物性别、α-突触核蛋白、DA 转运蛋白 (DAT) 和钙结合蛋白-D28k (Calb1)。我们使用快速扫描循环伏安法检测了小鼠纹状体切片中诱发的 DA 释放，并通过检测 LTCC 抑制剂伊拉地平或 CP8 对 DA 释放的抑制来评估 LTCC 对 DA 释放的支持。通过基因敲除或药理学操作，我们发现纹状体 LTCC 对 DA 释放的支持取决于多个交叉因素，以区域和性别不同的方式。 LTCC功能受到与帕金森病风险相关的因素的促进，包括男性、α-突触核蛋白、DAT和背外侧坐标，但受到与保护相关的因素的限制，即女性、葡萄糖脑苷脂酶活性、Calb1和腹内侧坐标。总之，这些数据表明 DA 轴突中的 LTCC 功能和伊拉地平效应是局部控制的，并表明它们的变化方式可能反过来影响或反映导致帕金森病变性的细胞应激。
Ca2+entry into nigrostriatal dopamine (DA) neurons and axons via L‐type voltage‐gated Ca2+channels (LTCCs) contributes, respectively, to pacemaker activity and DA release and has long been thought to contribute to vulnerability to degeneration in Parkinson's disease. LTCC function is greater in DA axons and neurons from substantia nigra pars compacta than from ventral tegmental area, but this is not explained by channel expression level. We tested the hypothesis that LTCC control of DA release is governed rather by local mechanisms, focussing on candidate biological factors known to operate differently between types of DA neurons and/or be associated with their differing vulnerability to parkinsonism, including biological sex, α‐synuclein, DA transporters (DATs) and calbindin‐D28k (Calb1). We detected evoked DA release ex vivo in mouse striatal slices using fast‐scan cyclic voltammetry and assessed LTCC support of DA release by detecting the inhibition of DA release by the LTCC inhibitors isradipine or CP8. Using genetic knockouts or pharmacological manipulations, we identified that striatal LTCC support of DA release depended on multiple intersecting factors, in a regionally and sexually divergent manner. LTCC function was promoted by factors associated with Parkinsonian risk, including male sex, α‐synuclein, DAT and a dorsolateral co‐ordinate, but limited by factors associated with protection, that is, female sex, glucocerebrosidase activity, Calb1 and ventromedial co‐ordinate. Together, these data show that LTCC function in DA axons and isradipine effect are locally governed and suggest they vary in a manner that in turn might impact on, or reflect, the cellular stress that leads to parkinsonian degeneration.