Pathophysiological consequences of isoform-specific IP receptor mutations.

Ca signaling governs a diverse range of cellular processes and, as such, is subject to tight regulation. A main component of the complex intracellular Ca-signaling network is the inositol 1,4,5-trisphosphate (IP) receptor (IPR), a tetrameric channel that mediates Ca release from the endoplasmic reticulum (ER) in response to IP. IPR function is controlled by a myriad of factors, such as Ca, ATP, kinases and phosphatases and a plethora of accessory and regulatory proteins. Further complexity in IPR-mediated Ca signaling is the result of the existence of three main isoforms (IPR1, IPR2 and IPR3) that display distinct functional characteristics and properties. Despite their abundant and overlapping expression profiles, IPR1 is highly expressed in neurons, IPR2 in cardiomyocytes and hepatocytes and IPR3 in rapidly proliferating cells as e.g. epithelial cells. As a consequence, dysfunction and/or dysregulation of IPR isoforms will have distinct pathophysiological outcomes, ranging from neurological disorders for IPR1 to dysfunctional exocrine tissues and autoimmune diseases for IPR2 and -3. Over the past years, several IPR 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 IPR isoform and the subsequent molecular mechanisms underlying the etiology of the disease.