Type 1 inositol 1,4,5-trisphosphate receptor knock-out mice: their phenotypes and their meaning in neuroscience and clinical practice

Cytoplasmic calcium, which acts as a second messenger, is derived not only from outside the cell but also from intracellular stores. A receptor for in ositol 1,4,5-trisphosphate (IP3), an intracellular second messenger, is loc ated on these internal calcium stores and functions as a calcium releasing channel. The "type 1" IP3 receptor (IP(3)R1) is concentrated predominantly in cerebellar Purkinje cells and is also widely present in other neural and peripheral tissues, but many of its physiological roles in these cells are still unclear. We have previously succeeded in obtaining mice with disrupt ion of this IP(3)R1 gene, in which brain IP3-induced calcium release was al most completely abolished. They were rarely born alive, indicating that IP( 3)R1 has some functions during embryonic development. Animals exhibited sev ere neurological symptoms, ataxia and epilepsy, and were shown to be defici ent in the cerebellar long-term depression. They give us promising clues re garding the physiological roles of calcium release from internal stores and serve as a model for the relevant human disease states.