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Am J Physiol Gastrointest Liver Physiol 294: G1362-G1368, 2008. First published April 24, 2008; doi:10.1152/ajpgi.00043.2008
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NEUROREGULATION AND MOTILITY

ATP induces guinea pig gallbladder smooth muscle excitability via the P2Y4 receptor and COX-1 activity

Aaron C. Bartoo,1 Mark T. Nelson,2 and Gary M. Mawe1,2

Departments of 1Anatomy and Neurobiology and 2Pharmacology, University of Vermont College of Medicine, Burlington, Vermont

Submitted 29 January 2008 ; accepted in final form 14 April 2008

The purpose of this study was to elucidate the mechanisms by which ATP increases guinea pig gallbladder smooth muscle (GBSM) excitability. We evaluated changes in membrane potential and action potential (AP) frequency in GBSM by use of intracellular recording. Application of ATP (100 µM) caused membrane depolarization and a significant increase in AP frequency that were not sensitive to block by tetrodotoxin (0.5 µM). The nonselective P2 antagonist, suramin (100 µM), blocked the excitatory response, resulting in decreased AP frequency in the presence of ATP. The excitatory response to ATP was not altered by pyridoxal-phosphate-6-azophenyl-2,4-disulfonic acid (30 µM), a nonselective P2X antagonist. UTP also caused membrane depolarization and increased AP frequency, with a similar dose-response relationship as ATP. RT-PCR demonstrated that the P2Y4, but not P2Y2, receptor subtype is expressed in guinea pig gallbladder muscularis. ATP induced excitation was blocked by indomethacin (10 µM) and the cyclooxygenase (COX)-1 inhibitor SC-560 (300 nM), but not the COX-2 inhibitor nimesulide (500 nM). These data suggest that ATP stimulates P2Y4 receptors within the gallbladder muscularis and, in turn, stimulate prostanoid production via COX-1 leading to increased excitability of GBSM.

biliary motility; cyclooxygenase; purinergic; P2Y; prostaglandins


Address for reprint requests and other correspondence: G. M. Mawe, Dept. of Anatomy and Neurobiology, Univ. of Vermont College of Medicine, 89 Beaumont Ave., D406 Given Bldg., Burlington, VT 05405 (e-mail: gary.mawe{at}uvm.edu)






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