Carbon monoxide activates human intestinal smooth muscle L-type Ca 2+ channels through a nitric oxide-dependent mechanism

Inja Lim, Simon J. Gibbons, Gregory L. Lyford, Steven M. Miller, Peter R. Strege, Michael G. Sarr, Suvro Chatterjee, Joseph H. Szurszewski, Vijay H. Shah, Gianrico Farrugia

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

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 Ca 2+ channel expressed in HEK cells and in native cells using the patch-clamp technique. Extracellular solution contained 10 mM Ba 2+ as the charge carrier. Maximal peak Ba 2+ current (I Ba) 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 I Ba, and CO (0.2%) increased NO production in transfected HEK cells. The CO-induced increase in I Ba 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 I Ba. 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 Ca 2+ 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.

Original languageEnglish (US)
Pages (from-to)G7-G14
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume288
Issue number1 51-1
DOIs
StatePublished - Jan 1 2005

Keywords

  • Gases
  • Human studies
  • Ion channels
  • Patch clamp

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

Fingerprint Dive into the research topics of 'Carbon monoxide activates human intestinal smooth muscle L-type Ca <sup>2+</sup> channels through a nitric oxide-dependent mechanism'. Together they form a unique fingerprint.

  • Cite this