Pharmacological and Biological Tools to Inhibit IP₃ Receptors

Inositol 1,4,5-trisphosphate receptors (IP₃Rs) are an important class of ion channels that mediate calcium (Ca²⁺) release from the endoplasmic reticulum and other organelles, thereby critically controlling cell function. Dysregulation of these channels, including excessive IP₃R activity, has been implicated in a plethora of diseases. The current arsenal of tools to acutely inhibit IP₃Rs consists of various antagonists with distinct mechanisms of action. Yet, most suffer from limited selectivity due to their impact on several other Ca²⁺-transport systems, cellular targets, and/or lack of membrane permeability. This shortage of highly specific IP₃R antagonists limits biomedical research and hampers the development of therapeutic strategies targeting IP₃R channels. This work aims to provide a comprehensive overview of IP₃R-antagonizing tools that were developed and characterized over the past decades, focusing on three classes of molecules: (1) pharmacological antagonists that directly affect IP₃Rs by binding to the channel, (2) biological antagonists that directly affect IP₃Rs by interacting with the IP₃R, and (3) antagonism of IP₃R activity via regulation of the phosphoinositide signaling pathway upstream of IP₃Rs.