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NEUROREGULATION AND MOTILITY
1Enteric NeuroScience Program, Mayo Clinic and Mayo Clinic College of Medicine, Rochester; 2Department of Physiology, College of Medicine, Chung-Ang University, Seoul, Korea; and 3Gastrointestinal Unit, Mayo Clinic and Mayo Clinic College of Medicine, Rochester, Minnesota
Submitted 5 May 2004 ; accepted in final form 11 August 2004
Carbon monoxide (CO) is increasingly recognized as a physiological messenger. CO is produced in the gastrointestinal tract with diverse functions, including regulation of gastrointestinal motility, interacting with nitric oxide (NO) to mediate neurotransmission. The aim of this study was to determine the effect of CO on the human intestinal L-type Ca2+ channel expressed in HEK cells and in native cells using the patch-clamp technique. Extracellular solution contained 10 mM Ba2+ as the charge carrier. Maximal peak Ba2+ current (IBa) was significantly increased by bath application of 0.2% CO to transfected HEK cells (18 ± 3%). The NO donor S-nitroso-N-acetylpenicillamine also increased IBa, and CO (0.2%) increased NO production in transfected HEK cells. The CO-induced increase in IBa was blocked when cells were pretreated with 1H-[1,2,4]-oxadiazolo[4,3-a]quinoxalin-1-one (10 µM) or inhibitors of NO synthase (NOS). The PKA inhibitor KT-5720 (0.5 µM) and milrinone (3 µM), a phosphodiesterase (PDE) III inhibitor, blocked the effect of CO on IBa. Similar effects were seen in freshly dissociated human intestinal smooth muscle cells. The data suggest that exogenous CO can activate native and heterologously expressed intestinal L-type Ca2+ channels through a pathway that involves activation of NOS, increased NO, and cGMP levels, but not PKG. Rather, the pathway appears to involve PKA, partly by reducing cAMP breakdown through inhibition of PDE III. CO-induced NO production may explain the apparent discrepancy between the low affinity of guanylyl cyclase for CO and the robust cGMP production evoked by CO.
ion channels; gases; human studies; patch clamp
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