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