Does Cavβ3 subunit confer neuroprotection in chronic inflammatory CNS disease?

传统上认为，电压门控钙通道的β亚基类型3(Cavβ3)在神经元中仅作为Cav通道，尤其是Cav2.2(N型)通道的调节亚单位发挥作用。然而，我们最近描述了一个新的作用，即细胞内1，4，5-三磷酸肌醇受体(IP3R)依赖的钙释放的调节，从而加深了我们对其在非神经细胞中功能的理解。在研究单位的第一个资助期，我们通过全球和细胞特异性基因敲除表明，CAVβ3决定了实验性自身免疫性脑脊髓炎(多发性硬化症的一种模型)的疾病进展。与各自的野生型相比，CAVβ3全球基因敲除后出现了更严重的EAE，其特征是脊髓和视神经中免疫细胞的渗透增加，但也增加了已经处于“健康”基因敲除状态的血脑屏障的通透性。整体CAVβ3基因敲除的EAE表型在神经元或T细胞特异性CAVβ3基因敲除中并不明显，但在星形胶质细胞和内皮细胞特异性基因敲除中都有反映。星形胶质细胞和内皮细胞参与血脑屏障的维持，为了进一步了解Cavβ3如何参与EAE的进展，我们将通过免疫组织化学和超微结构原位分析以及体外血脑屏障模型来研究Cavβ3在这些细胞中的可能功能，并寻求增强Cavβ3在体内疾病进展中的有利作用的策略。

The β subunit type 3 of voltage-gated Ca2+ channels (Cavβ3) has traditionally been understood to exclusively function as a regulatory subunit of Cav channels, especially of Cav2.2 (N-type) channels, in neurons. However, we recently described a novel role as a regulator of intracellular inositol 1,4,5-trisphosphate receptor (IP3R)-dependent Ca2+ release, thus furthering our understanding of its functions in non-neuronal cells. During the first funding period of the Research Unit, we showed through global and cell-specific knockouts that Cavβ3 determines the disease progression of experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. Cavβ3 global knockouts developed more severe EAE than their respective wild-types, characterised by increased immune cell infiltration in the spinal cord and the optic nerves, but also increased blood-brain barrier (BBB) permeability already in “healthy” knockouts. The EAE phenotype of the global Cavβ3 knockout was not apparent in neuron- or T cell-specific Cavβ3 knockouts, but was mirrored in both astrocyte- and endothelial-specific knockouts. Astrocytes and endothelial cells contribute to the maintenance of the BBB and in order to further our understanding of how Cavβ3 is involved in the progression of EAE we will investigate possible Cavβ3 functions in these cells by immunohistochemical and ultrastructural analysis in situ and BBB models in vitro and pursue strategies to boost the beneficial effect of Cavβ3 on disease progression in vivo.