STAC3 (SH3 and cysteine rich domain 3) is essential for normal skeletal muscle excitation-contraction coupling and calcium homeostasis. The protein functions as a critical regulator of voltage-gated calcium channels, particularly enhancing CACNA1S channel activity and promoting its membrane expression 1. STAC3 is required for normal Ca2+ release from the sarcoplasmic reticulum in response to membrane depolarization, which is fundamental for muscle contraction 2. Mechanistically, STAC3 interacts with the carboxy terminus of CaV1.1 channels through duplex signaling mechanisms involving both channel trafficking and gating modulation 1. The protein also slows inactivation rates of CACNA1C calcium channels. Mutations in STAC3 cause congenital myopathy 13, originally described as Native American myopathy, characterized by muscle weakness, contractures, and dysmorphisms 3 4. Additionally, STAC3 variants are associated with malignant hyperthermia susceptibility, a potentially fatal pharmacogenetic reaction to anesthetic agents 5 3. Conditional knockout studies demonstrate that STAC3 is crucial for postnatal muscle growth, fiber composition, and electrostimulation-induced calcium release, with deficiency leading to reduced muscle mass and strength 2. These findings establish STAC3 as a fundamental regulator of skeletal muscle calcium signaling and contractile function.