Document Detail

Regulation of pacemaker currents in interstitial cells of Cajal from murine small intestine by cyclic nucleotides.
MedLine Citation:
PMID:  10944178     Owner:  NLM     Status:  MEDLINE    
1. Electrical rhythmicity (slow waves) in gastrointestinal muscles (GI) is generated by interstitial cells of Cajal (ICC). Cultured ICC from the murine small intestine were studied with the patch-clamp technique to characterize regulation of pacemaker currents by cyclic nucleotides. Cyclic nucleotide agonists were also tested on intact strips of murine small intestine. 2. Nitric oxide donors slowed the frequency of pacemaker currents in a concentration-dependent manner. These effects depended on cGMP formation and were reduced by 1H-[1,2, 4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). The effects of nitric oxide donors were mimicked by membrane-permeable analogues of cGMP. The specific cGMP phosphodiesterase inhibitor zaprinast reduced the frequency of spontaneous pacemaker currents. 3. The cGMP-dependent effects on pacemaker currents were not affected by okadaic acid or KT-5823, an inhibitor of protein kinase G. 4. Forskolin, but not dideoxy forskolin, reduced the frequency of spontaneous pacemaker activity and activated a sustained outward current. The latter was likely to be due to ATP-dependent K+ channels because it was blocked by glibenclamide. 5. The effects of forskolin were not mimicked by membrane-permeable cAMP analogues. A membrane-permeable inhibitor of protein kinase A, myristoylated PKA inhibitor, and the adenylyl cyclase inhibitor SQ-22536, had no effect on responses to forskolin. 6. Responses of intact muscles to cGMP and cAMP agonists were similar to the responses of pacemaker cells. Changes in resting membrane potential and slow wave amplitude, however, were noted in intact jejunal muscles that were not observed in ICC. Differences in responses may have been due to the effects of cyclic nucleotide agonists on smooth muscle cells that would sum with responses of ICC in intact jejunal muscle strips. 7. A cGMP-dependent mechanism regulates slow wave frequency, but this occurs through direct action of cGMP not via protein phosphorylation. Regulation of pacemaker currents by cAMP-dependent mechanisms was not observed.
S D Koh; T W Kim; J Y Jun; N J Glasgow; S M Ward; K M Sanders
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The Journal of physiology     Volume:  527 Pt 1     ISSN:  0022-3751     ISO Abbreviation:  J. Physiol. (Lond.)     Publication Date:  2000 Aug 
Date Detail:
Created Date:  2000-10-05     Completed Date:  2000-11-07     Revised Date:  2013-06-11    
Medline Journal Info:
Nlm Unique ID:  0266262     Medline TA:  J Physiol     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  149-62     Citation Subset:  IM    
Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada 89557, USA.
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MeSH Terms
Adenylate Cyclase / antagonists & inhibitors
Cells, Cultured
Cyclic AMP / analogs & derivatives,  metabolism,  physiology
Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
Cyclic GMP / analogs & derivatives,  antagonists & inhibitors,  physiology*
Cyclic GMP-Dependent Protein Kinases / antagonists & inhibitors
Electric Conductivity*
Forskolin / pharmacology
Gastrointestinal Motility
Guanylate Cyclase / antagonists & inhibitors
Intestine, Small / cytology,  drug effects,  physiology*
Mice, Inbred BALB C
Nitric Oxide / metabolism
Nitroprusside / pharmacology
Nucleotides, Cyclic / agonists,  antagonists & inhibitors,  physiology*
Patch-Clamp Techniques
Phosphodiesterase Inhibitors / pharmacology
Grant Support
Reg. No./Substance:
0/Nucleotides, Cyclic; 0/Phosphodiesterase Inhibitors; 10102-43-9/Nitric Oxide; 15078-28-1/Nitroprusside; 60-92-4/Cyclic AMP; 66428-89-5/Forskolin; 7665-99-8/Cyclic GMP; EC AMP-Dependent Protein Kinases; EC GMP-Dependent Protein Kinases; EC Cyclase; EC Cyclase

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