Its three main effectors are PKA which phosphorylates numerous metabolic enzymes , EPAC a guanine-nucleotide-exchange factor , and cyclic-nucleotide-gated ion channels.
The intracellular levels of cAMP are regulated by the balance between the activities of two enzymes see Fig. Different isoforms of these enzymes are encoded by a large number of genes, which differ in their expression patterns and mechanisms of regulation, generating cell-type and stimulus-specific responses McKnight Crosstalk with other pathways provides further modulation of the signal strength and cell-type specificity, and feedforward signaling by PKA itself stimulates PDE4.
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Protein kinase PKA , the best-understood target, is a symmetrical complex of two regulatory R subunits and two catalytic C subunits there are several isoforms of both subunits. It is activated by the binding of cAMP to two sites on each of the R subunits, which causes their dissociation from the C subunits Taylor et al.
The catalytic activity of the C subunit is decreased by a protein kinase inhibitor PKI , which can also act as a chaperone and promote nuclear export of the C subunit, thereby decreasing nuclear functions of PKA.
They can also target it to particular subcellular locations and anchor it to ACs for immediate local activation of PKA or PDEs to create local negative feedback loops for signal termination Wong and Scott A large number of cytosolic and nuclear proteins have been identified as substrates for PKA Tasken et al.
PKA phosphorylates numerous metabolic enzymes, including glycogen synthase and phosphorylase kinase, which inhibits glycogen synthesis and promotes glycogen breakdown, respectively, and acetyl CoA carboxylase, which inhibits lipid synthesis.
PKA also regulates other signaling pathways. PKA also decreases the activities of Raf and Rho and modulates ion channel permeability.
Gs-Protein and Gi-Protein Coupled Signal Transduction
PKA-promoted phosphorylation can also increase the activity of PP2A as part of a negative feedback mechanism. A major function of Rap1 is to increase cell adhesion via integrin receptors how this occurs is unclear Bos Finally, cAMP can bind to and modulate the function of a family of cyclic-nucleotide-gated ion channels. These are relatively nonselective cation channels that conduct calcium.
The channels are also permeable to sodium and potassium, which can alter the membrane potential in electrically active cells.
Figure 2 adapted from Fimia and Sassone-Corsi Additional Perspectives on Signal Transduction available at www. National Center for Biotechnology Information , U. Cold Spring Harb Perspect Biol. Paolo Sassone-Corsi.
Altered Signal Transduction in Heart Disease
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Abstract cAMP was the first second messenger to be identified. Open in a separate window.
ch 11 cAMP Pathway
Figure 1. Figure 2.
Acknowledgments Figure 2 adapted from Fimia and Sassone-Corsi Cyclic AMP signaling. Transcriptional regulation by the phosphorylation-dependent factor CREB.
Cyclic AMP second messenger systems. Seven-transmembrane receptors.
Second Messengers - The cAMP and Ca Pathways [HD Animation]
Transcription factors responsive to cAMP. Fractionation and characterization of a cyclic adenine ribonucleotide formed by tissue particles. Structure, function and regulation of human cAMP-dependent protein kinases.
Structural framework for the protein kinase family. AKAP signaling complexes: Focal points in space and time. Cross-talk between cellular signaling pathways suggested by phorbol-ester induced adenylate cyclase phosphorylation.
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