Prolyl Oligopeptidase, Inositol Phosphate Signalling and Lithium Sensitivity

Adrian      J. Harwood

Abstract

Inhibition of prolyl oligopeptidase (PO) elevates inositol phosphate (IP) signalling and reduces cell sensitivity to lithium (Li+). This review discusses recent evidence that shows PO acts via the multiple inositol polyphosphate phosphatase (MIPP) to regulate gene expression. As a consequence, PO inhibition causes both a transient, rapid increase in I(1,4,5)P3 and a long-term elevation of IP signalling. This pathway is evolutionary conserved, being present in both the social amoeba Dictyostelium and human cell systems, and has potential implications for mental health.

Keywords: Bipolar mood disorder, Dictyostelium, inositol phosphate signalling, lithium, multiple inositol polyphosphate phosphatase, prolyl oligopeptidase, IMPase, LY294002, GSK-3, MIPP, ISYNA1