Regulation of Cav2.1 by Ankyrin B and its variants




Choi, Catherine S.W.

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Ankyrin B (AnkB) is a scaffolding protein, acting as a bridge between ion channels and cytoskeleton networks. AnkB variants are associated with cognitive disorders including autism spectrum disorder and epilepsy. In the brain, AnkB interacts with Cav2.1, the pore-forming subunit of P/Q type voltage gated calcium channels. However, how AnkB regulates Cav2.1 is not fully understood. Using HEK293T cells, we discovered that AnkB increases Cav2.1 expression levels but does not change Cav2.1 surface levels. AnkB p.S646F increases Cav2.1 to an even greater level of expression, again without impacting Cav2.1 surface levels. Looking at a partial loss of AnkB in glutamatergic neurons, overall Cav2.1 levels decreased at P30 but the synaptosomal fraction was not impacted. Our findings indicate that AnkB plays a role in regulating an intracellular pool of Cav2.1 but does not affect the surface or the synaptosomal pools of Cav2.1. This intracellular pool of Cav2.1 may play an important role in neuronal function and homeostasis, suggesting a mechanism for neuronal pathogenicity of AnkB variants.



Ankyrin B, Cav2.1, CACNA1A, intracellular pool, surface localization, synapse