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1 Enteric NeuroScience Program, Mayo Clinic and Mayo Clinic College of Medicine, Rochester, MN, USA; Deparment of Physiology, Chung-Ang University, College of Medicine, Seoul, Republic of Korea
2 Enteric NeuroScience Program, Mayo Clinic and Mayo Clinic College of Medicine, Rochester, MN, USA
3 Enteric NeuroScience Program, Mayo Clinic and Mayo Clinic College of Medicine, Rochester, MN, USA; GI Unit, Mayo Clinic and Mayo Clinic College of Medicine, Rochester, MN, USA
4 GI Unit, Mayo Clinic and Mayo Clinic College of Medicine, Rochester, MN, USA
* To whom correspondence should be addressed. E-mail: farrugia.gianrico{at}mayo.edu.
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 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 current (IBa) was significantly increased by bath application of 0.2 % CO to transfected HEK cells (18 ± 3%). The nitric oxide (NO) donor SNAP 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 ODQ (10 µM) or inhibitors of nitric oxide synthase (NOS). The protein kinase A (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 protein kinase G. 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.
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