Proteinase-activated receptors

Proteinase-activated receptors are a recently described, novel family of se ven-transmembrane G-protein-coupled receptors. Rather then being stimulated through ligand receptor occupancy, activation is initiated by cleavage of the N terminus of the receptor by a serine protease resulting in the genera tion of a new tethered ligand that interacts with the receptor within extra cellular loop-2. To date, four proteinase-activated receptors (PARs) have b een identified, with distinct N-terminal cleavage sites and tethered ligand pharmacology. In addition to the progress in the generation of PAR-1 antag onists, we describe the role of thrombin in such processes as wound healing and the evidence implicating PAR-1 in vascular disorders and cancer. We al so identify advances in the understanding of PAR-1-mediated intracellular s ignaling and receptor desensitization. The cellular functions, signaling ev ents, and desensitization processes involved in PARS activation are also as sessed. However, other major aspects of PAR-2 are highlighted, in particula r the ability of several serine protease enzymes, in addition to trypsin, t o function as activators of PAR-2, The likely physiological and pathophysio logical roles for PAR-2 in shin, intestine, blood vessels, and the peripher al nervous system are considered in the context of PAR-2 activation by mult iple serine proteases. The recent discovery of PAR-3 and PAR-4 as additiona l thrombin-sensitive PARs further highlights the complexity in assessing th e effects of thrombin in several different systems, an issue that remains t o be fully addressed. These discoveries have also highlighted possible PAR- PAR interactions at both functional and molecular levels. The future identi fication of other PARs and their modes of activation are an important futur e direction for this expanding field of study.