[Physiology of protease-activated receptors (PARs): involvement of PARs in digestive functions].
The protease-activated receptor (PAR), a G protein-coupled receptor present on cell surface, mediates cellular actions of extracellular proteases. Proteases cleave the extracellular N-terminal of PAR molecules at a specific site, unmasking and exposing a novel N-terminal, a tethered ligand, that binds to the body of receptor molecules resulting in receptor activation. Amongst four distinct PARs that have been cloned, PARs 1, 3 and 4 are activated by thrombin, but PAR-2 is activated by trypsin or mast cell tryptase. Human platelets express two distinct thrombin receptors, PAR-1 and PAR-4, while murine platelets express PAR-3 and PAR-4. Apart from roles of PARs in platelet activation, PARs are distributed to a number of organs in various species, predicting their physiological importance. We have been evaluating agonists specific for each PAR, using multiple procedures including a HEK cell calcium signal receptor desensitization assay. Using specific agonists that we developed, we found the following: 1) the salivary glands express PAR-2 mRNA and secret saliva in response to PAR-2 activation; 2) pancreatic juice secretion occurs following in vivo PAR-2 activation; 3) PAR-1 and PAR-2 modulate duodenal motility. Collectively, PAR plays various physiological and/or pathophysiological roles, especially in the digestive systems, and could be a novel target for drug development.
Kawabata
A
A
Department of Pathophysiology & Therapeutics, Faculty of Pharmaceutical Sciences, Kinki University, Higashi-Osaka, Japan.
Kuroda
R
R
Hollenberg
M D
MD
D000818:Animals; D005769:Gastrointestinal Motility / Q000502:physiology*; D006801:Humans; D051379:Mice; D010179:Pancreas / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; D018179:Receptors, Thrombin / Q000187:drug effects / Q000502:physiology*; D012469:Salivary Glands / Q000737:chemistry; D012472:Salivation / Q000502:physiology*
D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; D018179:Receptors, Thrombin