Lithium and the Phosphoinositide Cycle: an Example of Uncompetitive Inhibition and Its Pharmacological Consequences

The ability of lithium to exert profound and selective psychopharmacological effects to ameliorate manic-depressive psychosis has been the focus of considerable research effort. There is increasing evidence that lithium exerts its therapeutic action by interfering with polyphosphoinositide metabolism in brain and prevention of inositol recycling by an uncompetitive inhibition of inositol monophosphatase. Stefan Nahorski, Ian Ragan and John Challiss discuss this unusual stimulus-dependent form of enzyme inhibition, emphasizing that the selectivity exhibited by lithium depends upon the degree of inositol lipid hydrolysis and polyphosphoinositide dephosphorylation.