CACNA2D1, encoding the α2δ-1 protein, is a gene for an auxiliary subunit of voltage-gated calcium channels. These channels are crucial for calcium ion influx, which is involved in numerous cellular processes like corticogenesis, transcription, and synaptogenesis [4]. The α2δ subunits play important roles in the trafficking and function of the calcium channel complexes [2].

In disease-related studies, knockdown of CACNA2D1 in human colon cancer cell lines HCT116 and RKO decreased cell proliferation and migration, increased the number of cells in the sub-G1 phase and induced apoptosis, indicating its role in colon cancer progression [1]. In gastric cancer cell lines MKN7 and HGC27, CACNA2D1-depleted cells also showed suppressed proliferation, migration, invasion and induced apoptosis. The apoptosis signaling pathway was enhanced via p53, BAX, and caspase 3 in these cells [3]. Biallelic loss-of-function variants in CACNA2D1 in two individuals caused early-onset developmental epileptic encephalopathy [2]. In mouse hippocampal neurons, cigarette smoke-induced activation of the ΔFOSB-CACNA2D1 axis led to calcium overload and cognitive impairment [5]. Nerve injury in rats promoted Cacna2d1 transcription in dorsal root ganglia by reducing HDAC2 occupancy at its promoter [6].

In summary, CACNA2D1 is essential for the normal function of voltage-gated calcium channels and thus various biological processes. Studies using loss-of-function models, such as knockdown in cell lines and biallelic loss-of-function variants in individuals, have revealed its significant roles in cancers, neurodevelopmental disorders, cognitive impairment, and neuropathic pain, highlighting its potential as a biomarker and therapeutic target in these disease areas.