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TARGETING HPCAL4 AS A THERAPEUTIC STRATEGY FOR <EM>CACNA1A</EM>-RELATED DISORDERS
Anna Maienzaand 6 co-authors
University of Trieste
FENS Forum 2026 (2026)
Barcelona, Spain
Board PS04-08PM-273
Presentation
Date TBA
Board: PS04-08PM-273
Event Information
Poster Board
PS04-08PM-273
Poster
View posterAbstract
Voltage-gated P/Q-type calcium channels (CaV2.1), encoded by CACNA1A, control presynaptic calcium influx and neurotransmitter release in most brain regions. Loss-of-function mutations in CACNA1A cause neurological disorders including episodic ataxia type 2 and epileptic encephalopathy 42. Current therapies, such as acetazolamide and 4-aminopyridine, show limited efficacy and significant side effects, highlighting the need for mechanism-based alternatives.
Here, we define the interactome of the neuronal calcium sensor protein HPCAL4 and assess its potential to functionally compensate for CACNA1A loss-of-function mutations by enhancing CaV2.1 trafficking and activity.
Wild-type and mutant CaV2.1 channels (S218L, F1491S, F1406C, E147K) were expressed as SNAP-tagged constructs in primary neurons to quantify dendritic and axonal membrane localization by structured illumination microscopy. In parallel, primary neurons expressing SNAP or HPCAL4-SNAP were subjected to pull-down and mass spectrometry to map protein-protein interactions. To assess direct binding, SNAP-tagged CaV2.1 C-terminal fragments were co-expressed with EGFP-HPCAL4 in heterologous expression systems, followed by pull-down and western blot.
Loss-of-function CaV2.1 mutants showed reduced axonal surface expression compared with wild-type channels. Proteomic analyses identified CaV2.1 in the HPCAL4 interactome, and HPCAL4 displayed preferential binding to the CaV2.1 C-terminal tail in heterologous expression systems, providing a rationale to assess whether HPCAL4 can rescue defects associated with mutant CaV2.1 channels.
Together, these data identify HPCAL4 as a promising modulator of CaV2.1 in CACNA1A channelopathies.
Here, we define the interactome of the neuronal calcium sensor protein HPCAL4 and assess its potential to functionally compensate for CACNA1A loss-of-function mutations by enhancing CaV2.1 trafficking and activity.
Wild-type and mutant CaV2.1 channels (S218L, F1491S, F1406C, E147K) were expressed as SNAP-tagged constructs in primary neurons to quantify dendritic and axonal membrane localization by structured illumination microscopy. In parallel, primary neurons expressing SNAP or HPCAL4-SNAP were subjected to pull-down and mass spectrometry to map protein-protein interactions. To assess direct binding, SNAP-tagged CaV2.1 C-terminal fragments were co-expressed with EGFP-HPCAL4 in heterologous expression systems, followed by pull-down and western blot.
Loss-of-function CaV2.1 mutants showed reduced axonal surface expression compared with wild-type channels. Proteomic analyses identified CaV2.1 in the HPCAL4 interactome, and HPCAL4 displayed preferential binding to the CaV2.1 C-terminal tail in heterologous expression systems, providing a rationale to assess whether HPCAL4 can rescue defects associated with mutant CaV2.1 channels.
Together, these data identify HPCAL4 as a promising modulator of CaV2.1 in CACNA1A channelopathies.
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