title: The soluble guanylyl cyclase activator YC-1 increases intracellular cGMP and cAMP via independent mechanisms in INS-1E cells.
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.
authors.affiliation: Department of Pharmacology, Weill Medical College of Cornell University, New York, New York 10065, USA.
authors.forename: Lavoisier S
authors.initials: LS
authors.lastname: Ramos-Espiritu
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Hess
authors.forename: Jochen
authors.initials: J
authors.lastname: Buck
authors.forename: Lonny R
authors.initials: LR
authors.lastname: Levin
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism*; D020536:Enzyme Activators / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000378:metabolism*; D007191:Indazoles / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D010078:Oxazines / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D014158:Transcription, Genetic
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; C450679:BAY 41-8543; D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D007191:Indazoles; D009025:Morpholines; C111257:NS 2028; D010069:Oxadiazoles; D010078:Oxazines; D011743:Pyrimidines; D011810:Quinoxalines; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D000242:Cyclic AMP; D020928:Mitogen-Activated Protein Kinases; D010727:Phosphoric Diester Hydrolases; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D005947:Glucose