Cyclic AMP is both a pro-apoptotic and anti-apoptotic second messenger

Acta Physiol (Oxf). 2012 Feb;204(2):277-87. doi: 10.1111/j.1748-1716.2011.02273.x. Epub 2011 May 26.


The second messenger cyclic AMP (cAMP) can either stimulate or inhibit programmed cell death (apoptosis). Here, we review examples of cell types that show pro-apoptotic or anti-apoptotic responses to increases in cAMP. We also show that cells can have both such responses, although predominantly having one or the other. Protein kinase A (PKA)-promoted changes in phosphorylation and gene expression can mediate pro-apoptotic responses, such as in murine S49 lymphoma cells, based on evidence that mutants lacking PKA fail to undergo cAMP-promoted, mitochondria-dependent apoptosis. Mechanisms for the anti-apoptotic response to cAMP likely involve Epac (Exchange protein activated by cAMP), a cAMP-regulated effector that is a guanine nucleotide exchange factor (GEF) for the low molecular weight G-protein, Rap1. Therapeutic approaches that activate PKA-mediated pro-apoptosis or block Epac-mediated anti-apoptotisis may provide a means to enhance cell killing, such as in certain cancers. In contrast, efforts to block PKA or stimulate Epac have the potential to be useful in diseases settings (such as heart failure) associated with cAMP-promoted apoptosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Apoptosis Regulatory Proteins / metabolism
  • Apoptosis*
  • Cyclic AMP / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Guanine Nucleotide Exchange Factors / metabolism
  • Mitochondria / metabolism
  • Phosphorylation / physiology
  • Second Messenger Systems / physiology*
  • rap1 GTP-Binding Proteins / metabolism


  • Apoptosis Regulatory Proteins
  • Guanine Nucleotide Exchange Factors
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • rap1 GTP-Binding Proteins