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.
Footnotes
This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant GM62328]; the National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development [Grant HD059913]; and the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant NS055255] (all to J.B. and L.R.L.).
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.111.184135.
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ABBREVIATIONS:
- YC-1
- 5-[1-(phenylmethyl)-1H-indazol-3-yl]-2-furanmethanol
- sGC
- soluble guanylyl cyclase
- NO
- nitric oxide
- ERK
- extracellular signal-regulated kinase
- PDE
- phosphodiesterase
- MAPK
- mitogen-activated protein kinase
- sAC
- soluble adenylyl cyclase
- ODQ
- 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one
- NS2028
- 8-bromo-4H-2,5-dioxa-3,9b-diaza-cyclopenta[a]naphthalen-1-one
- BAY 41-8543
- 2-[1-[(2-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-(4-morpholinyl)-4,6-pyrimidinediamine
- SNAP
- S-nitroso-N-acetylpenicillamine
- 2′,5′-ddAdo
- 2′,5′-dideoxyadenosine
- IBMX
- 3-isobutyl-1-methylxanthine
- KH7
- 2-(1H-benzimidazol-2-ylthio)-2-[(5-bromo-2-hydroxyphenyl)methylene]hydrazide propanoic acid
- AC
- adenylyl cyclase
- sACt
- truncated soluble adenylyl cyclase
- sACfl
- full-length soluble adenylyl cyclase
- tmAC
- transmembrane adenylyl cyclase.
- Received May 16, 2011.
- Accepted June 9, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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