Inositol 1,4,5-Trisphosphate Receptor Mutations Associated with Human Disease: Insights into Receptor Function and Dysfunction

Inositol 1,4,5-trisphosphate receptors (IP 3 Rs) are ubiquitous intracellular Ca 2+ release channels. Their activation, subcellular localization, abundance, and regulation play major roles in defining the spatiotemporal characteristics of intracellular Ca 2+ signals, which are in turn fundamental to the appropriate activation of effectors that control a myriad of cellular events. Over the past decade, ∼100 mutations in ITPR s associated with human diseases have been documented. Mutations have been detailed in all three IP 3 R subtypes and all functional domains of the protein, resulting in both gain and loss of receptor function. IP 3 R mutations are associated with a diverse array of pathology including spinocerebellar ataxia, peripheral neuropathy, immunopathy, anhidrosis, hyperparathyroidism, and squamous cell carcinoma. This review focuses on how studying the altered activity of these mutations provides information relating to IP 3 R structure and function, the physiology underpinned by specific IP 3 R subtypes, and the pathological consequences of dysregulated Ca 2+ signaling in human disease.