STAC2 (SH3 and cysteine-rich domain 2) is a calcium channel regulatory protein that plays multiple roles in cellular calcium signaling. In neurons, STAC2 suppresses calcium-dependent inactivation (CDI) of L-type calcium channels (CaV1.2 and CaV1.3) through direct interaction with the channel's C terminus, thereby tuning calcium entry into cells 1. STAC2 expression increases substantially in the adult forebrain and cerebellum compared to neonatal levels, suggesting developmental regulation of neuronal calcium signaling 1. Outside the nervous system, STAC2 promotes expression and membrane localization of the skeletal muscle calcium channel CACNA1S and interacts with the dihydropyridine receptor's II-III loop domain, contributing to excitation-contraction coupling 2. Disease relevance includes Martorell hypertensive ischemic leg ulcers, where STAC2 is significantly upregulated perivascularly, suggesting increased calcium influx contributes to pathogenesis and implicating calcium channel antagonists as potential therapeutics 3. STAC2 has also been identified as a differentially expressed gene in heart failure, breast cancer, ovarian cancer, and colorectal cancer contexts, though its specific pathogenic roles in these conditions require further investigation 4, 5, 6, 7. Clinically, STAC2 may serve as a prognostic biomarker in multiple cancer types.