In addition to increasing cGMP, the soluble guanylyl cyclase (sGC) activator 3-(5'-Hydroxymethyl-2'-furyl)-1-benzyl indazole (YC-1) can elevate intracellular cAMP levels. This response was assumed to be as a result of cGMP dependent inhibition of a cAMP phosphodiesterases (PDE); however, in this study we show that YC-1 induced cAMP production in the rat pancreatic beta cell line, INS-1E cells occurs independent of its function as sGC activator and independent of its ability to inhibit PDEs. This YC1-induced cAMP increase is dependent upon soluble adenylyl cyclase (sAC) and not on transmembrane adenylyl cyclase (tmAC) activity. We previously showed sAC-generated cAMP can lead to ERK activation, and YC-1 stimulated cAMP production also stimulates ERK. While 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.
- Received May 16, 2011.
- Revision received June 8, 2011.
- Accepted June 9, 2011.
- The American Society for Pharmacology and Experimental Therapeutics