The cAMP/PKA Pathway Intracellular Signaling System

The cAMP/PKA pathway is an intracellular signaling system involved in regulating many of the functions of eukaryotic cells.10 When a G-protein–coupled receptor on the surface of a cell binds to its particular ligand, the receptor may stimulate the intracellular production of cAMP by the adenylyl cyclase associated with that receptor.10 cAMP can then diffuse through the cytoplasm, where it interacts with various targets. Thus, cAMP serves as a second messenger within a cell. The most common downstream effector of cAMP is PKA.10, 74 When a molecule of PKA binds to four molecules of cAMP, the PKA molecule releases two subunits that have enzyme activity on target proteins.76

How can each GPCR transmit a specific signal even though so many different GPCRs are using the same second messenger? Theoretically, each cell might express only a few of the possible GPCRs, only a few of the possible PKAs, and only a few of the downstream targets. Also, the various PKAs are anchored to specific structures within the cell by A-kinase anchoring proteins (AKAPs).76 Thus, a GPCR might send a specific message by creating a cAMP gradient within a specific location within a particular kind of cell. The cAMP gradients are regulated by enzymes from a large and complex superfamily called the cyclic nucleotide phosphodiesterase enzymes (PDEs), some of which degrade cAMP to AMP. Others degrade cyclic guanine monophosphate (cGMP), which can also serve as a second messenger.

The PDEs are a large and diverse group of enzymes. Because of their diversity, which allows specific distribution at cellular and subcellular levels, PDEs can selectively regulate various cellular functions.28

PDE4 could play a role in regulating the inflammation that occurs in a number of inflammatory diseases, including psoriasis, psoriatic arthritis, and ankylosing spondylitis.

PDE4 Promotes Inflammation by Degrading cAMP Within Immune Cells

Phosphodiesterase 4 (PDE4) is the predominant cAMP-degrading enzyme expressed in inflammatory cells.1

Numerous studies have shown that cAMP helps to regulate T cell function.29

It is thought that cAMP helps to maintain immune homeostasis by suppressing the release of proinflammatory mediators (eg, TNF-α, IL-17, and IFN-γ)1 and promoting the release of anti-inflammatory mediators (eg, IL-10)6 by immune cells.

In vitro studies suggest that cAMP exerts these effects mainly through PKA. Once activated by cAMP, the PKA translocates into the cell nucleus and activates a transcription factor called CREB (cAMP response element binding protein). CREB plus a coactivator called CREB-binding protein (CBP) then bind to a cAMP response element (CRE) in the promoter region of a gene. A decrease in PDE4 activity can lead to increased levels of cAMP, which in turn leads to increased transcription of genes that have CRE sites within their promoters, including the gene for IL-10, which is an anti-inflammatory mediator.77

In contrast, cAMP elevation would tend to inhibit the expression of genes that are driven primarily by the transcription factor nuclear factor κ B (NF-κB), including the genes for some important proinflammatory mediators, because it is believed that the NF-κB p65 subunit must compete with CREB for CPB.75

By decreasing the intracellular level of cAMP, PDE4 could prevent PKA from modulating pro- and anti-inflammatory mediators released by a cell, resulting in a proinflammatory response where anti-inflammatory mediators are down-regulated and proinflammatory mediators are upregulated.

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Glossary:

Cyclic adenosine monophosphate (cAMP)

An activator of phosphorylase kinase and an effector of other enzymes, formed in muscle from ATP by adenylate cyclase and broken down to 5'‑AMP by a phosphodiesterase; the first known second messenger, it is a regulator of metabolism. A related compound (2',3') is also known.

Adenosine monophosphate (AMP), or adenylic acid

A condensation product of adenosine and phosphoric acid; a nucleotide found among the hydrolysis products of all nucleic acids. 3'‑Adenylic acid (adenosine 3'‑monophosphate) and 5'‑adenylic acid [adenosine 5'‑monophosphate (AMP)] differ in the place of attachment of the phosphoric acid to the D‑ribose; deoxyadenylic acid differs in having H instead of OH at the 2' position of D‑ribose.

Cyclic AMP Response Element-Binding Protein (CREB)

A protein that has been shown to function as a calcium-regulated transcription factor as well as a substrate for depolarization-activated calcium-calmodulin-dependent protein kinases. This protein functions to integrate both calcium and cAMP signals.

Cyclic guanosine monophosphate (cGMP)

an analogue of cAMP; a second messenger for atrial natriuretic factor.

Inflammation (or inflammatory response)

The general term for histologically apparent cytologic changes, cellular infiltration, and mediator release that occurs in affected blood vessels and adjacent tissue in response to injury or abnormal stimulation. The so‑called cardinal signs of rubor (redness), calor (heat), tumor (swelling), and dolor (pain) may or may not be present.

Interferons (IFN)

Cytokines produced by T cells, fibroblasts, and other cells in response to viral infection and other biologic and synthetic stimuli; IFNs bind to specific receptors on cell membranes.

Interleukin (IL)

Any of a group of multifunctional cytokines synthesized by lymphocytes, monocytes, macrophages, and lymphoid and nonlymphoid cells.

Intracellular

Within a cell or cells.

Phosphodiesterase (PDE)

Enzymes that cleave bonds in phosphodiesters, such as those in cAMP.

Phosphodiesterase 4 (PDE4)

A key enzyme involved in the cytokine production of inflammatory cells. PDE4 is an intracellular enzyme that promotes inflammation by degrading intracellular levels of cyclic adenosine monophosphate (cAMP), a naturally occurring second messenger that helps maintain immune homeostasis by modulating the production of pro‑ and anti‑inflammatory mediators.

Protein kinase A (PKA)

A group of enzymes that are dependent on cyclic AMP and catalyze the phosphorylation of serine or threonine residues on proteins. Included under this category are two cyclic‑AMP‑dependent protein kinase subtypes, each of which is defined by its subunit composition.

Tumor necrosis factor (TNF)

Any of several cytokines that function as cell‑associated or secreted proteins interacting with receptors of the tumor necrosis factor receptor (TNFR) family.

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References:

  1. 1 Bäumer W, Hoppmann J, Rundfeldt C, Kietzmann M. Highly selective phosphodiesterase 4 inhibitors for the treatment of allergic skin diseases and psoriasis. Inflamm Allergy Drug Targets. 2007;6:17‑26.
  2. 6 Oger S, Mehats C, Dallot E, Cabrol D, Leroy MJ. Evidence for a role of phosphodiesterase 4 in lipopolysaccharide‑stimulated prostaglandin E2 production and matrix metalloproteinase‑9 activity in human amniochorionic membranes. J Immunol. 2005;174:8082‑8089.
  3. 10 Taskén K, Aandahl EM. Localized effects of cAMP mediated by distinct routes of protein kinase A. Physiol Rev. 2004;84:137‑167.
  4. 28 Houslay MD, Adams DR. PDE4 cAMP phosphodiesterases: modular enzymes that orchestrate signalling cross‑talk, desensitization and compartmentalization. Biochem J. 2003;370:1‑18.
  5. 29 Mosenden R, Tasken K. Cyclic AMP‑mediated immune regulation‑‑overview of mechanisms of action in T cells. Cell Signal. 2011;23:1009‑1016.
  6. 74 Oliveira RF, Terrin A, Di Benedetto G, Cannon RC, Koh W, et al. The role of type 4 phosphodiesterases in generating microdomains of cAMP: large scale stochastic simulations. PLoS ONE. 2010;5(7):e11725.
  7. 75 Parry GC, Mackman N. Role of cyclic AMP response element‑binding protein in cyclic AMP inhibition of NF‑κB‑mediated transcription. J Immunol. 1997;159(11):5450‑5456.
  8. 76 Skålhegg BS, Taskén K. Specificity in the cAMP/PKA signaling pathway. Differential expression, regulation, and subcellular localization of subunits of PKA. Front Biosci. 2000;5:D678‑D693.
  9. 77 Brenner S, Prösch S, Schenke‑Layland K, et al. cAMP‑induced interleukin‑10 promoter activation depends on CCAAT/enhancer‑binding protein expression and monocytic differentiation. J Biol Chem. 2003;278(8):5597‑5604.