Chapter 1 : Introduction to Second Messengers: Lessons from Cyclic AMP

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Introduction to Second Messengers: Lessons from Cyclic AMP, Page 1 of 2

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At the turn of the 21st century, researchers linked the second messenger bis-(3',5') cyclic diguanylic acid (also known as cyclic di-GMP [c-di-GMP]) to proteins that contained either the GGDEF domain, the EAL domain, or both and showed that these proteins were ubiquitous. Researchers had reported that epinephrine was produced by the adrenal gland and that this epinephrine traveled from the adrenal gland to the liver cells that store glycogen; however, the mechanism by which epinephrine elicited this effect remained unknown. Today, the mammalian cyclic AMP (cAMP) signal transduction network is known to include a dizzying array of G-protein-coupled receptors, a plethora of G-protein subunits, 10 adenylyl cyclases (9 membrane bound and 1 cytosolic), 11 PDE families, and multiple cAMP effectors, including PKA, PKC, diverse guanine exchange factors, and a variety of cyclic nucleotide-gated ion channels. The parallels between the mammalian cAMP network and the bacterial systems centered on c-di-GMP are striking. One obvious reason to compartmentalize proteins within microdomains is to bring related signaling components into close proximity. The mammalian plasma membrane is heterogeneous. This heterogeneity is produced, in part, by the concentration to specific locations of large amounts of cholesterol and sphingolipids. Two major hypotheses have been proposed to explain the ability of PDEs to shape cAMP gradients: the barrier hypothesis and the sink hypothesis.

Citation: Wolfe A. 2010. Introduction to Second Messengers: Lessons from Cyclic AMP, p 3-7. In Wolfe A, Visick K (ed), The Second Messenger Cyclic Di-GMP. ASM Press, Washington, DC. doi: 10.1128/9781555816667.ch1
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Image of Figure 1.
Figure 1.

Models for cAMP-based signal transduction. (A) The simple model. An extracellular stimulus, e.g., norepinephrine (N), binds to and activates an integral membrane G-protein-associated receptor (black). The associated G protein (G) transduces that information to an integral membrane adenylyl cyclase (AC), which uses ATP to synthesize cAMP, which is degraded to 5′c-AMP by a soluble PDE. Thus, the balance between synthesis and degradation sets the concentration of cAMP, which binds to an effector, e.g., PKC. PKC activates the process by which glycogen becomes metabolized to glucose. (B) The barrier hypothesis. PDEs anchored to the membrane or to the cytoskeleton form an enzymatic barrier around an AC such that the cAMP synthesized by the associated AC remains localized. Thus, only effectors located in the vicinity of the AC become activated. (C) The sink hypothesis. PDE activity depletes its neighborhood of cAMP, ensuring that colocalized effectors do not become activated.

Citation: Wolfe A. 2010. Introduction to Second Messengers: Lessons from Cyclic AMP, p 3-7. In Wolfe A, Visick K (ed), The Second Messenger Cyclic Di-GMP. ASM Press, Washington, DC. doi: 10.1128/9781555816667.ch1
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