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This Article Full Text Full Text (PDF) All Versions of this Article: 293/6/H3471    most recent 00357.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Liu, G. X. Articles by Coetzee, W. A. Search for Related Content PubMed PubMed Citation Articles by Liu, G. X. Articles by Coetzee, W. A.

Modulation of human cardiovascular outward rectifying chloride channel by intra- and extracellular ATP

¹Cardiovascular Research Center, Rhode Island Hospital, Providence, Rhode Island; ²Columbia University Medical Center, New York, New York; ³Department of Pediatrics, University of Iowa, Iowa City, Iowa; and ⁴Departments of Pediatrics, Pharmacology, and Physiology and Neuroscience, New York University School of Medicine, New York, New York

Submitted 21 March 2007 ; accepted in final form 11 October 2007

The macroscopic volume-regulated anion current (VRAC) is regulated by both intracellular and extracellular ATP, which has important implications in signaling and regulation of cellular excitability. The outwardly rectifying Cl^– channel (ORCC) is a major contributor to the VRAC. This study investigated the effects of intracellular and extracellular ATP on the ORCCs expressed in the human cardiovascular system. With inside-out single-channel patch-clamp techniques, ORCCs were recorded from myocytes isolated from human atrium and septal ventricle and from primary cells originating from human coronary artery endothelium and human coronary artery smooth muscle. ORCCs from all of these tissues had similar biophysical properties, i.e., they were outwardly rectifying in symmetrical Cl^– solutions, exhibited a slope conductance of 90–100 pS at positive potentials and 22 pS at negative potentials, and had a high open probability that was independent of voltage or time. The presence of ATP at the cytosolic face of the membrane increased the number of patches that contained functional ORCC but had no effect on gating. In contrast, "extracellular" ATP (in pipette solution) had no effect on the proportion of patches in which ORCC was detected but strongly reduced the open probability by increasing the closed dwell time. The potency order for nucleotides to affect gating was ATPS > ATP = UTP > ADP > AMP, which suggests that a negatively charged phosphate group is involved in ORCC block. Our findings are consistent with a role of ORCC in the human cardiovasculature (atrium, ventricle, and coronary arteries). Regulation of ORCC by extracellular ATP suggests that this channel may have an important role in maintaining electrical activity and membrane potential under conditions in which extracellular ATP levels are elevated, such as with ATP release from nerve endings or during pathophysiological conditions.

human heart; atrial myocytes; ventricular myocytes; endothelial cells; smooth muscle cells