Physiology and Pharmacology Publications
Proteinases as hormones: Targets and mechanisms for proteolytic signaling
Document Type
Conference Proceeding
Publication Date
8-1-2008
Journal
Biological Chemistry
Volume
389
Issue
8
First Page
971
Last Page
982
URL with Digital Object Identifier
10.1515/BC.2008.120
Abstract
Proteinases, such as kallikrein-related peptidases, trypsin and thrombin, can play hormone-like 'messenger' roles in vivo. They can regulate cell signaling by cleaving and activating a novel family of G-protein-coupled proteinase-activated receptors (PARs 1-4) by unmasking a tethered receptor-triggering ligand. Short synthetic PAR-derived peptide sequences (PAR-APs) can selectively activate PARs 1, 2 and 4, causing physiological responses in vitro and in vivo. Using the PAR-APs to activate the receptors in vivo, it has been found that PARs, like hormone receptors, can affect the vascular, renal, respiratory, gastrointestinal, musculoskeletal and nervous systems (central and peripheral). PARs trigger responses ranging from vasodilatation to intestinal inflammation, increased cytokine production and increased nociception. These PAR-stimulated responses have been implicated in various disease states, including cancer, atherosclerosis, asthma, arthritis, colitis and Alzheimer's disease. In addition to targeting the PARs, proteinases can also cause hormone-like effects by other signaling mechanisms that may be as important as the activation of PARs. Thus, the PARs themselves, their activating serine proteinases and their signaling pathways can be considered as attractive targets for therapeutic drug development. Further, proteinases can be considered as physiologically relevant 'hormone-like' messengers that can convey signals locally or systemically either via PARs or by other mechanisms. © 2008 by Walter de Gruyter.