Here, we combine gene expression studies, immunoblotting, immunocytochemistry and live cell Ca2+ imaging to show (i) the role of CaV2.2 channels for presynaptic Ca2+ flux in hippocampal cultures, (ii) upregulation of CaV2.2 channels mediates increased Ca2+ flux during HSP, (iii) HSP downregulates endogenous α2δ‐1 subunits at synapses in hippocampal cultures, and (iv) overexpression of α2δ‐1 decreases the contribution of CaV2.2 to presynaptic Ca2+ flux and abolishes the effect of TTX to elevate Ca2+ transients. This evidence concerns the gene CACNA1B and hereditary spastic paraplegia.