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Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada 89557
Swelling-activated or volume-sensitive
Cl
currents are found in
numerous cell types and play a variety of roles in their function; however, molecular characterization of the channels is generally lacking. Recently, the molecular entity responsible for
swelling-activated Cl
current in cardiac myocytes has been identified as ClC-3. The goal of
our study was to determine whether such a channel exists in smooth
muscle cells of the canine colon using both molecular biological and
electrophysiological techniques and, if present, to characterize its
functional and molecular properties. We hypothesized that ClC-3 is
present in colonic smooth muscle and is regulated in a manner similar
to the molecular entity cloned from heart. Indeed, the ClC-3 gene was
expressed in colonic myocytes, as demonstrated by reverse transcriptase
polymerase chain reaction performed on isolated cells. The current
activated by decreasing extracellular osmolarity from 300 to 250 mosM
was outwardly rectifying and dependent on the
Cl gradient. Current
magnitude increased and reversed at more negative potentials when
Cl was replaced by
I or
Br. Tamoxifen
([Z]-1-[p-dimethylaminoethoxy-phenyl]-1,2-diphenyl-1-butene; 10 µM) and DIDS (100 µM) inhibited the current, whereas 25 µM niflumic acid, 10 µM nicardipine, and
Ca2+ removal had no effect.
Current was inhibited by 1 mM extracellular ATP in a voltage-dependent
manner. Cl current was also
regulated by protein kinase C, as phorbol 12,13-dibutyrate (300 nM)
decreased Cl current
magnitude, while chelerythrine chloride (30 µM) activated it under
isotonic conditions. Our findings indicate that a current activated by
hypotonic solution is present in colonic myocytes and is likely
mediated by ClC-3. Furthermore, we suggest that the ClC-3 may be an
important mechanism controlling depolarization and contraction of
colonic smooth muscle under conditions that impose physical stress on
the cells.
chloride channels; adenosine 5'-triphosphate; protein kinase C; myogenic response; gastrointestinal motility
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