| Protein kinase A binds cAMP and phosphorylates other enzymes
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| cAMP transduces its effects on glycogen-glucose interconversion by regulating a key signaling enzyme, protein kinase A (PKA), which phosphorylates target proteins on serine and threonine residues. PKA is a multimeric enzyme comprising two regulatory (R) subunits and two catalytic (C) subunits: the R2C2 tetrameric form of PKA is inactive, but binding of four molecules of cAMP to the R subunits leads to the release of catalytically active C-subunits, which can then phosphorylate and modulate the activity of two key enzymes, phosphorylase kinase and glycogen synthase (see Fig. 38.5), which are involved in regulation of glycogen metabolism (see Chapter 12). Involvement of such a multilayered signal transduction cascade leads to substantial amplification of the original signal at each stage of the cascade (Fig. 38.6), ensuring that binding of only a few hormone molecules leads to release of a large number of sugar molecules.
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| Figure 38.5 Protein kinase A (PKA) acts as a signaling enzyme for the second messenger, cAMP. Binding of a stimulatory G-protein (Gs) to the hormone-receptor complex activates adenylyl cyclase, which catalyses the production of cAMP. Protein kinase A is activated by binding four molecules of cAMP. Translocation of PKA into the nucleus modulates activity of transcription factors - for example CREB and ATF (see text) - leading to induction or repression of gene expression. |
| Many other cellular responses can be mediated by the cAMP-PKA signaling cassette
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| PKA-mediated phosphorylation can regulate the activity of a number of ion channels, such as K+, Cl- and Ca2+ channels, and that of phosphatases involved in the regulation of cell signaling. In addition, translocation of PKA into the nucleus allows modulation of the activity of transcription factors such as the cAMP-responsive-element-binding protein (CREB) or the activation transcription factor (ATF) families, leading to either the induction or the repression of expression of specific genes (see Fig. 38.5 and Chapter 33).
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Figure 38.6 Signal cascade induces amplification of hormone signal. Each activated hormone-receptor complex can stimulate multiple Gs molecules. Each adenylyl cyclase can catalyze the generation of many cAMP molecules, and each protein kinase A can activate many phosphorylase molecules, leading to the release of a large number of glucose molecules (G) as a result of glycogen degradation. |
| Transcription requires binding of RNA polymerase (RNApol) to non-transcribed regions of the gene, called promoters, which are located upstream (5') of the start site. Transcription factors are activators or repressors of gene expression that act by altering the rate of formation of the basal transcriptional complex on the promoter (Chapter 32). Transcription factors binding to regulatory sites on DNA can therefore be regarded as passwords that cooperatively open multiple locks to give RNA polymerase access to specific genes. It should be noted that binding of multiple transcription factors might be required for the induction of a single gene; hence, activation of different combinations of transcription factors provides the specificity for the switching on of particular genes in response to different hormones or growth factors.
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| The amplification of a hormonal signal involving G-proteins, adenylyl cyclase, protein kinase A and phosphorylase is illustrated in Fig. 38.6 (compare Fig. 12.4).
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