A-kinase–anchoring proteins serve to localize PKA as well as PDEs within specific cellular microdomains, thereby creating discrete subcellular pools of intracellular cAMP and its effector within a cell.
#Cyclic amp free#
Binding of cAMP to the regulatory subunit of protein kinase A (PKA) leads to dissociation of its catalytic subunit, which is then free to phosphorylate specific Ser and Thr residues on numerous target proteins, including the transcription factor cAMP response element–binding protein ( 9). Moreover, because both ACs and PDEs can be localized to different spatial compartments within the cell, the evanescent presence of cAMP can be further regulated at a subcellular level ( see below) ( 8).ĭiverse cAMP effector molecules also contribute to the complexity of this pathway. There are 11 distinct PDE gene families whose expression is likewise tissue-specific. PDEs oppose cAMP signaling by degrading intracellular cAMP ( 7). Intracellular levels of cAMP are tightly regulated, not only by AC but also by the enzyme phosphodiesterase (PDE) ( Figure 1). To date there are 10 known AC isoforms that are differentially expressed in various cell types ( 6). Depicted here is a pattern demonstrated for alveolar macrophages in which specific antimicrobial functions are differentially regulated by particular cAMP effectors. The downstream signaling of cAMP is mediated by its interactions with effector molecules, protein kinase A (PKA) or exchange proteins directly activated by cAMP (Epac), which have been shown to modulate phagocyte functions. PDE inhibitors prevent such degradation, resulting in accumulation of intracellular cAMP. Phosphodiesterases (PDEs), which degrade cAMP to AMP, are another regulator of intracellular cAMP levels. Pertussis toxin and cholera toxin cause elevated cAMP levels through ADP-ribosylation of either the Gαi subunit to prevent its inhibition of AC or of the Gαs subunit to constitutively activate AC, respectively. The production of cAMP is also regulated by microbial pathogens. The binding of the Gα subunit to adenylyl cyclase (AC) either stimulates (Gαs) or inhibits (Gαi) the enzyme's generation of cAMP. The binding of an agonist to the G protein–coupled receptor (GPCR) induces a conformational change resulting in the liberation of the Gα subunit from the βγ subunit complex. The regulation of cyclic AMP (cAMP) levels and antimicrobial actions. By contrast, Gαi subunits inhibit AC and the production of cAMP some well-known Gαi-coupled GPCR ligands include chemokines CCR1–10 and CXCR1–6 as well as leukotrienes B 4, C 4, and D 4 ( 4). Some of the well-known Gαs-coupled GPCR ligands include epinephrine and norepinephrine, histamine, serotonin, and certain cycloxygenase (COX)-derived prostaglandins (particularly prostaglandin E 2 and I 2 ) ( 4). The free Gαs subunit stimulates the enzyme adenylyl cyclase (AC) to catalyze the cyclization of ATP to generate cAMP and pyrophosphate ( 5, 6). Ligand binding results in the exchange of GDP for GTP on the Gαs protein and its subsequent dissociation from the βγ subunit complex ( 4). The generation of cAMP is initiated when an extracellular first messenger (neurotransmitter, hormone, chemokine, lipid mediator, or drug) binds to a seven transmembrane–spanning G protein–coupled receptor (GPCR) that is coupled to a stimulatory G protein α subunit (Gαs) ( Figure 1). Although many contemporary reviews on innate immunity focus on pathogen recognition receptors and signaling pathways ( 3), the importance of cAMP as a controller derives from its ability to exert broad modulatory effects that are independent of the pathogen, the recognition receptor, or the signaling pathway in question. This review will address cAMP regulation of innate immunity, with an emphasis on the lung. Biological processes mediated by this second messenger include memory, metabolism, gene regulation, and immune function ( 2). cAMP is now recognized as a universal regulator of cellular function in organisms including amoebas, plants, and humans ( 1). Sutherland was awarded the 1971 Nobel Prize for this work, which would prove to be the first of five Nobel Prizes recognizing research on this molecule. Sutherland during his studies of the mechanisms of hormone action. The cyclic nucleotide cyclic adenosine monophosphate (cAMP)-the original member of the family of second messengers-was discovered by Dr. This review will provide clinicians with an overview of the cyclic AMP axis, its role as a down-regulator of host antimicrobial defense functions, and the clinical and translational relevance of such actions.
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