The soluble guanylyl cyclase activator YC-1 increases intracellular cGMP and cAMP via independent mechanisms in INS-1E cells

J Pharmacol Exp Ther. 2011 Sep;338(3):925-31. doi: 10.1124/jpet.111.184135. Epub 2011 Jun 10.

Abstract

In addition to increasing cGMP, the soluble guanylyl cyclase (sGC) activator 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1) can elevate intracellular cAMP levels. This response was assumed to be as a result of cGMP-dependent inhibition of cAMP phosphodiesterases; however, in this study, we show that YC-1-induced cAMP production in the rat pancreatic beta cell line INS-1E occurs independent of its function as a sGC activator and independent of its ability to inhibit phosphodiesterases. This YC-1-induced cAMP increase is dependent upon soluble adenylyl cyclase and not on transmembrane adenylyl cyclase activity. We previously showed that soluble adenylyl cyclase-generated cAMP can lead to extracellular signal-regulated kinase activation and that YC-1-stimulated cAMP production also stimulates extracellular signal-regulated kinase. Although YC-1 has been used as a tool for investigating sGC and cGMP-mediated pathways, this study reveals cGMP-independent pharmacological actions of this compound.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Line
  • Cyclic AMP / metabolism*
  • Cyclic GMP / metabolism*
  • Enzyme Activators / pharmacology*
  • Enzyme Inhibitors / pharmacology
  • Glucose / pharmacology
  • Guanylate Cyclase / metabolism*
  • Indazoles / pharmacology*
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism*
  • Mitogen-Activated Protein Kinases / metabolism
  • Morpholines / pharmacology
  • Oxadiazoles / pharmacology
  • Oxazines / pharmacology
  • Phosphoric Diester Hydrolases / metabolism
  • Pyrimidines / pharmacology
  • Quinoxalines / pharmacology
  • Rats
  • Transcription, Genetic

Substances

  • 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one
  • BAY 41-8543
  • Enzyme Activators
  • Enzyme Inhibitors
  • Indazoles
  • Morpholines
  • NS 2028
  • Oxadiazoles
  • Oxazines
  • Pyrimidines
  • Quinoxalines
  • 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole
  • Cyclic AMP
  • Mitogen-Activated Protein Kinases
  • Phosphoric Diester Hydrolases
  • Guanylate Cyclase
  • Cyclic GMP
  • Glucose