Agonists of protease-activated receptors 1 and 2 stimulate electrolyte secretion from mouse gallbladder

Kirkland, J. G., Cottrell, G. S. ORCID: https://orcid.org/0000-0001-9098-7627, Bunnett, N. W. and Corvera, C. U. (2007) Agonists of protease-activated receptors 1 and 2 stimulate electrolyte secretion from mouse gallbladder. American Journal of Physiology Gastrointestinal and Liver Physiology, 293 (1). G335-G346. ISSN 0193-1857 doi: 10.1152/ajpgi.00425.2006

Abstract/Summary

Cholecystitis is one of the most common gastrointestinal diseases. Inflammation induces the activation of proteases that can signal to cells by cleaving protease-activated receptors (PARs) to induce hemostasis, inflammation, pain, and repair. However, the distribution of PARs in the gallbladder is unknown, and their effects on gallbladder function have not been fully investigated. We localized immunoreactive PAR(1) and PAR(2) to the epithelium, muscle, and serosa of mouse gallbladder. mRNA transcripts corresponding to PAR(1) and PAR(2), but not PAR(4), were detected by RT-PCR and sequencing. Addition of thrombin and a PAR(1)-selective activating peptide (TFLLRN-NH(2)) to the serosal surface of mouse gallbladder mounted in an Ussing chamber stimulated an increase in short-circuit current in wild-type but not PAR(1) knockout mice. Similarly, serosally applied trypsin and PAR(2) activating peptide (SLIGRL-NH(2)) increased short-circuit current in wild-type but not PAR(2) knockout mice. Proteases and activating peptides strongly inhibited electrogenic responses to subsequent stimulation with the same agonist, indicating homologous desensitization. Removal of HCO(3)(-) ions from the serosal buffer reduced responses to thrombin and trypsin by >80%. Agonists of PAR(1) and PAR(2) increase intracellular Ca(2+) concentration in isolated and cultured gallbladder epithelial cells. The COX-2 inhibitor meloxicam and an inhibitor of CFTR prevented the stimulatory effect of PAR(1) but not PAR(2). Thus PAR(1) and PAR(2) are expressed in the epithelium of the mouse gallbladder, and serosally applied proteases cause a HCO(3)(-) secretion. The effects of PAR(1) but not PAR(2) depend on generation of prostaglandins and activation of CFTR. These mechanisms may markedly influence fluid and electrolyte secretion of the inflamed gallbladder when multiple proteases are generated.

Additional Information	Full text freely available via DOI or PUBMED (see related URLs) Kirkland, Jacob G Cottrell, Graeme S Bunnett, Nigel W Corvera, Carlos U DK 43207/DK/NIDDK NIH HHS/ DK 57840/DK/NIDDK NIH HHS/ Am J Physiol Gastrointest Liver Physiol. 2007 Jul;293(1):G335-46. Epub 2007 Apr 12.
Item Type	Article
URI	https://reading-clone.eprints-hosting.org/id/eprint/30267
Item Type	Article
Refereed	Yes
Divisions	Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy > Division of Pharmacology No Reading authors. Back catalogue items
Uncontrolled Keywords	Animals Cells, Cultured Cyclooxygenase Inhibitors/pharmacology Electrolytes/*metabolism Epithelial Cells/drug effects Gallbladder/drug effects/*secretion Immunohistochemistry Male Mice Oligopeptides/pharmacology Receptor, PAR-1/*agonists/biosynthesis Receptor, PAR-2/*agonists/biosynthesis Thrombin/metabolism Trypsin/metabolism
Additional Information	Full text freely available via DOI or PUBMED (see related URLs) Kirkland, Jacob G Cottrell, Graeme S Bunnett, Nigel W Corvera, Carlos U DK 43207/DK/NIDDK NIH HHS/ DK 57840/DK/NIDDK NIH HHS/ Am J Physiol Gastrointest Liver Physiol. 2007 Jul;293(1):G335-46. Epub 2007 Apr 12.
Publisher	American Physiology Society
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