The inositol trisphosphate receptor gene family: implications for normal and abnormal brain function.

1. The phosphatidyl inositol (PI) second messenger system has been extensively investigated in the past decade. This complex pathway results in the production of two second messengers, one of which, inositol 1,4,5-trisphosphate, will be the focus of this review. 2. The intracellular receptor for this second messenger (IP3R) has been purified, reconstituted and extensively characterized in both brain and peripheral tissues. 3. Localization and functional studies show that IP3 binding causes the receptor to release portions of the intracellular calcium stores. 4. Multiple modulators of the receptor have been identified, including pH, calcium concentration, adenine nucleotide concentration and phosphorylation. 5. The cDNA for this molecule has been cloned from a number of sources. Studies of the molecular structure of the receptor have revealed additional levels of complexity including multiple alternative splicing events in the initially cloned cerebellar (Type I) receptor, as well as the existence of highly related but distinct cDNAs which likely reflect a gene family. 6. There is suggestive evidence linking the PI system, and thus the IP3R, to bipolar disorder and the actions of lithium.