PROLYL
OLIGOPEPETIDASE, INOSITOL PHOSPHATES AND LITHIUM
Adrian J.
Harwood
MRC
Laboratory for Cell Biology & Dept of Biology, University College London,
London, UK
Understanding the mechanism of lithium therapy will not only lead to design of
better pharmaceutical agents, but also should lead to understanding of the
underlying origins of disorders and biochemical based diagnostic assays. Recent
experiments have established that the cytosolic enzyme prolyl oligopeptidase
(PO) is a component of a novel signal transduction pathway that regulates basal
inositol metabolism and gene expression. Loss of PO confers resistance to the
mood stabilizer lithium and valproic acid (VPA), whereas PO over-expression
cause hypersensitivity. Interestingly the activity of this enzyme is reduced in
patients treated for bipolar depression, suggesting that lower activity may be
associated with the origins of their illness. I will discuss our latest findings
on prolyl oligopeptidase function.