RYR3 is a large homotetrameric calcium-release channel located in the endoplasmic/sarcoplasmic reticulum membrane 1. It mediates calcium-induced calcium release (CICR) to regulate intracellular Ca2+ levels across diverse cell types 2. In skeletal muscle, RYR3 is upregulated during early development and contributes to muscle contraction 2. In the brain, RYR3 localizes to hippocampal dendritic spines where it regulates synaptic plasticity 2. RYR3 also controls myogenic tone in arteries and participates in mast cell activation via MRGPRX2-mediated calcium mobilization 3. Structurally, RYR3 exhibits a unique functional profile with high sensitivity to activating ligands and high open probability, along with reduced binding affinity to the auxiliary protein FKBP12.6 2. Disease associations include congenital myopathy 20, with RYR3 disease-causing mutations concentrated in cytoplasmic domains that alter channel sensitivity to Ca2+ activation 1. RYR3 variants are associated with hypertension, type 2 diabetes, and Alzheimer's disease risk, implicating altered calcium signaling in these conditions 4. Rare RYR3 mutations have been identified in gender dysphoria patients, though mechanistic links remain unclear 5. The N-terminal region contains ligand-binding sites for chloride and ATP, with variants linked to epileptic encephalopathy 2.