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Logo of jbcThe Journal of Biological Chemistry
J Biol Chem. 2015 November 27; 290(48): 28642.
PMCID: PMC4661379

cAMP Elicits a Partially Agonistic Response with Protein Kinase G

Mechanism of cAMP Partial Agonism in Protein Kinase G (PKG)

See referenced article, J. Biol. Chem. 2015, 290, 28631–28641

The second messenger cyclic GMP (cGMP) binds to protein kinase G (PKG) to regulate signaling pathways that control a number of intracellular processes such as cell differentiation, platelet activation, and vasodilation. However, the mechanism for the selective activation of PKG by cGMP rather than by the other common second messenger cyclic AMP (cAMP) is not fully understood. Specifically, although the C-terminal cyclic nucleotide-binding domain of PKG exhibits a higher binding affinity for cGMP than for cAMP, the intracellular concentration of cAMP tends to be higher than that of cGMP which can permit cAMP-dependent activation of PKG in cells. In this Paper of the Week, Giuseppe Melacini at McMaster University and colleagues demonstrated that cAMP is a partial agonist of PKG and elucidated a mechanism for the partial agonism of cAMP. The investigators identified that cAMP-bound PKG dynamically exchanges between inactive, active, and partially autoinhibited states to elicit the partial agonism. The authors say, “By populating this third conformation, and to a lesser degree the inactive conformation, cAMP reduces the overall level of PKG activity compared to cGMP, thereby providing an explanation for the observed partial agonism of cAMP.”

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Schematic summary of the proposed model for cAMP partial agonism, illustrating the “inactive” (red) and “active” (green) conformational states explored in the cGMP-modulated two-state activation equilibrium and the additional “intermediate” state (orange) stabilized in the presence of cAMP.

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