Inositol phosphate receptors and calcium disposition in the brain

Abstract

In recent years it has become increasingly apparent that the phosphoinositide (PI) cycle represents a major second messenger system, comparable in importance to CAMP for actions of hormones, neurotransmitters, and other regulatory molecules. The PI cycle responds to the actions of an agonist at a membrane receptor that, via coupling to a G-protein, triggers the hydrolysis of phosphatidylinositol bisophosphate, resulting in the generation of inositol 1,4,5trisphosphate (IP,) and diacylglycerol (DAG). DAG enhances the activity of protein kinase C (PKC) by rendering it more sensitive to stimulation by Ca*+ (Nishizuka, 1988), while IP, stimulates the release of CaZ+ from endoplasmic reticulum (ER) stores (Berridge, 1987; Berridge and Irvine, 1989). The Ca2+ released by IP, stimulation activates many calcium-dependent processes. For instance, it enhances the phosphorylation of diverse substrates by PKC. IP, can be further phosphorylated to form inositol 1,3,4,Qetrakisphosphate (IP,), inositol 1,3,4,5,6-pentakisphosphate (IP,), and inositol hexakisphosphate (IP,). These higher inositol phosphates are present in the brain and other tissues in concentrations comparable to those of IP,, and so they may have comparably important functions, which have not been established, however. Clarification of physiological functions for the PI cycle has emerged mainly from studies of PI metabolism or turnover in response to various stimuli. In brain tissue, PI turnover had usually been monitored by labeling the inositol-containing phospholipids with the precursor 3H-inositol (Berridge et al., 1982). At the steady state, 3H-inositol is present in the various inositol phosphates, whose levels can be monitored in various ways. It is also possible to monitor PI turnover by using 3H-cytidine as an IP precursor. Cytidine feeds into the PI cycle via cytidine diphosphate diacylglycerol (CDP-DAG), whose levels increase with the rate of PI turnover (Godfrey, 1989). Since CDP-DAG is membrane bound, 3H-CDP-DAG localization by autoradiography can monitor PI turnover at the cellular level (Hwang et al., 1990). Such autoradiographic localization in the cerebellum reveals selective glutamatergic stimulation of PI turnover in Purkinje cells and their processes. In the hippocampus, both muscarinic cholinergic stimulation and glutamatergic stimulation increase PI turnover, but their sites of action differ, with