Actions of insulin-like growth factor binding protein-5 (IGFBP-5) are potentially regulated by tissue kallikrein in rat brains

Tissue kallikrein (EC 3.4.21.35) that hydrolyzes kininogen and releases a physiologically active peptide, kinin, is found in rat brains. Insulin-like growth factor binding proteins (IGFBPs) that modulate IGF actions are also expressed in a variety of tissues including rat brains, and one of the major IGFBPs expressed in brain is known to be IGFBP-5, which is reported to be hydrolyzed in vitro by prostate-specific antigen (PSA) and gamma-nerve growth factor (gamma-NGF), both of which belong to the member of the kallikrein gene family. This study was designed to determine whether or not kallikrein has a potential to hydrolyze IGFBP-5 and their topographic proximity was investigated in rat brain using double immunohistochemical staining method. Immunohistochemically, IGFBP-5 positive cells were numerous and widespread in the cerebral cortex and belonged to neurons in the cell configuration. IGFBP-5 positive cells were negative for S-100 protein and were positive for betaIII tubulin, confirming them to be neurons. In addition, kallikrein positive cells were virtually all IGFBP-5 positive cells. IGFBP-5 was clearly hydrolyzed by kallikrein with cleavage sites of Arg188-Met189 and Arg136-Arg137 of IGFBP-5. Therefore, there is a possibility that kallikrein plays an important role in brain physiology, specifically in the neurons by regulating the actions of IGFBP-5 and IGF.