Abstract
We have evaluated the hypothesis that cGMP may serve as an intracellular messenger regulating the viability of pancreatic beta-cells. A direct activator of soluble guanylyl cyclase, YC-1, caused a time- and dose-dependent loss of viability in clonal BRIN-BD11 beta-cells. This was accompanied by a rise in cGMP and was antagonised by Rp-8-pCPT-cGMPS, a selective inhibitor of protein kinase G (PKG). Reverse transcription polymerase chain reaction analysis confirmed that BRIN-BD11 cells (and human islets) express all three known isoforms of PKG (PKG-Ialpha, -Ibeta and II). Cell death induced by YC-1 was not sensitive to cell-permeable caspase inhibitors and was not accompanied by oligonucleosomal DNA fragmentation. The response was, however, inhibited by actinomycin D, suggesting that a transcription-dependent pathway of programmed cell death is involved in the actions of cGMP.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Cell Line
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Cell Survival
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Cyclic GMP / analogs & derivatives*
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Cyclic GMP / pharmacology
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Cyclic GMP / physiology*
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Cyclic GMP-Dependent Protein Kinase Type I
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Cyclic GMP-Dependent Protein Kinase Type II
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Cyclic GMP-Dependent Protein Kinases / drug effects
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Cyclic GMP-Dependent Protein Kinases / physiology*
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Dactinomycin / pharmacology
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Guanylate Cyclase / drug effects
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Indazoles / pharmacology
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Insulin / metabolism
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Insulin Secretion
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Islets of Langerhans / cytology*
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Islets of Langerhans / metabolism
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Protein Isoforms / analysis
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Rats
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Signal Transduction / physiology*
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Thionucleotides / pharmacology
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Transcription, Genetic
Substances
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8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphorothioate
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Indazoles
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Insulin
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Protein Isoforms
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Thionucleotides
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3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole
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Dactinomycin
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Cyclic GMP-Dependent Protein Kinase Type I
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Cyclic GMP-Dependent Protein Kinase Type II
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Cyclic GMP-Dependent Protein Kinases
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PRKG1 protein, human
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PRKG2 protein, human
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Prkg2 protein, rat
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Guanylate Cyclase
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Cyclic GMP