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FIGURE 16.3 Signal routing to cAMP involves different isoforms of adenylyl cyclase. Different isoforms of adenylyl cyclase produce cAMP in
response to differing signals received from G protein-coupled receptors (GPCRs), receptor channels (e.g., NMDA receptors) as well as receptors tyrosine
kinase (RTKs). This ability to integrate signals coming from many pathways to regulate the levels of cAMP-dependent protein kinase (PKA) activity
results in control of many physiological functions (figure redrawn from [29] and [20] ).
respect to its substrates. Although cAMP is the only acti-
vator of PKA, scaffold regulatory proteins can control the
temporal and spatial dynamics of PKA activation in
response to specific stimuli. The coordinated actions of
adenylyl cyclases and phosphodiesterases generate gradi-
ents and compartmentalized pools of cAMP, while AKAPs
maintain the PKA holoenzyme at specific intracellular sites
[42] . The AKAPs have two types of protein sequences that
regulate PKA function: a conserved amphipathic helix that
binds the R subunit dimer of the PKA holoenzyme, and
a specialized targeting region that enables individual
PKA
AKAP in an inactive state at a defined intracellular loca-
tion, where it is positioned to respond to cAMP by the local
release of active C subunit. Thus, with appropriate scaf-
folding, a protein kinase with broad substrate specificity
can rapidly phosphorylate specific targets in specific loca-
tions in response to a defined signal. Overall scaffolds serve
as building blocks for molecular complexes that integrate
and split signals. Such an assembly provides a natural
mechanism to achieve selective separation of signaling
components and thereby achieve specificity of signal
routing. The scaffolds also provide a mechanism by which
signals can be spatially resolved within the cell and thus
provide the spatial dimension to signaling networks.
AKAP complexes to bind specific subcellular
structures [36,43] . As a consequence, PKA is held by the
e
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