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LIVER AND BILIARY TRACT

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

Departments of ¹Surgery and ²Physiology, University of California San Francisco, and ³Veterans Affairs Medical Center, San Francisco, California

Submitted 13 September 2006 ; accepted in final form 12 April 2007

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 PAR₁ and PAR₂ to the epithelium, muscle, and serosa of mouse gallbladder. mRNA transcripts corresponding to PAR₁ and PAR₂, but not PAR₄, were detected by RT-PCR and sequencing. Addition of thrombin and a PAR₁-selective activating peptide (TFLLRN-NH₂) to the serosal surface of mouse gallbladder mounted in an Ussing chamber stimulated an increase in short-circuit current in wild-type but not PAR₁ knockout mice. Similarly, serosally applied trypsin and PAR₂ activating peptide (SLIGRL-NH₂) increased short-circuit current in wild-type but not PAR₂ knockout mice. Proteases and activating peptides strongly inhibited electrogenic responses to subsequent stimulation with the same agonist, indicating homologous desensitization. Removal of HCO₃^– ions from the serosal buffer reduced responses to thrombin and trypsin by >80%. Agonists of PAR₁ and PAR₂ increase intracellular Ca²⁺ concentration in isolated and cultured gallbladder epithelial cells. The COX-2 inhibitor meloxicam and an inhibitor of CFTR prevented the stimulatory effect of PAR₁ but not PAR₂. Thus PAR₁ and PAR₂ are expressed in the epithelium of the mouse gallbladder, and serosally applied proteases cause a HCO₃^– secretion. The effects of PAR₁ but not PAR₂ 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.

bicarbonate transport; epithelial transport