Pathophysiological consequences of isoform-specific IP3 receptor mutations

Ca2+ signaling governs a diverse range of cellular processes and, as such, is subject to tight regulation. A main component of the complex intracellular Ca2+-signaling network is the inositol 1,4,5-trisphosphate (IP3) receptor (IP3R), a tetrameric channel that mediates Ca2+ release from the endoplasmic reticulum (ER) in response to IP3. IP3R function is controlled by a myriad of factors, such as Ca2+, ATP, kinases and phosphatases and a plethora of accessory and regulatory proteins. Further complexity in IP3R-mediated Ca2+ signaling is the result of the existence of three main isoforms (IP(3)R1, IP(3)R2 and IP(3)R3) that display distinct functional characteristics and properties. Despite their abundant and overlapping expression profiles, IP3R1 is highly expressed in neurons, IP(3)R2 in cardiomyocytes and hepatocytes and IP(3)R3 in rapidly proliferating cells as e.g. epithelial cells. As a consequence, dysfunction and/or dysregulation of IP3R isoforms will have distinct pathophysiological outcomes, ranging from neurological disorders for IP(3)R1 to dysfunctional exocrine tissues and autoimmune diseases for IP(3)R2 and -3. Over the past years, several IP3R mutations have surfaced in the sequence analysis of patient derived samples. Here, we aimed to provide an integrative overview of the clinically most relevant mutations for each IP3R isoform and the subsequent molecular mechanisms underlying the etiology of the disease.