Does Cavβ3 subunit confer neuroprotection in chronic inflammatory CNS disease?

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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.