Pharmacology of inositol trisphosphate receptors

Abstract.

In almost all cells, cytosolic Ca²⁺ is a crucial intracellular messenger, regulating many cellular processes. In non-excitable as well as in some excitable cells, Ca²⁺ release from the intracellular stores into the cytoplasm is primarily initiated by the second messenger inositol 1,4,5-trisphosphate (IP₃), which interacts with the IP₃ receptor (IP₃R), a tetrameric intracellular Ca²⁺-release channel. This review focuses on the pharmacological modulation of the various functionally important sub-domains of the IP₃R, including the IP₃-binding domain, calmodulin-binding sites, adenine nucleotide-binding sites and the sites for interaction for FK506-binding proteins and other regulators. We will particularly focus on the pharmacological tools that interfere with these domains and discuss their relative specificity for the IP₃R, thereby indicating their potential usefulness for unraveling the complex functional regulation of the IP₃R.