cAMP Signaling Video

Cyclic adenosine monophosphate (cAMP, cyclic AMP or 3'-5'-cyclic adenosine monophosphate) is a second messenger important in many biological processes. cAMP is derived from adenosine triphosphate (ATP) and used for intracellular signal transduction in many different organisms, conveying the cAMP-dependent pathway.
cAMP is synthesised from ATP by adenylyl cyclase located on the inner side of the phospholipid bilayer. Adenylyl cyclase is activated by a range of signaling molecules through the activation of adenylyl cyclase stimulatory G (Gs)-coupled receptors and inhibited by agonists of adenylyl cyclase inhibitory G (Gi)-protein-coupled receptors. Liver adenylyl cyclase responds more strongly to glucagon, and muscle adenylyl cyclase responds more strongly to adrenaline.



Each PKA is a holoenzyme that consists of two regulatory and two catalytic subunits. Under low levels of cAMP, the holoenzyme remains intact and is catalytically inactive. When the concentration of cAMP rises (e.g., activation of adenylate cyclases by G protein-coupled receptors coupled to Gs, inhibition of phosphodiesterases that degrade cAMP), cAMP binds to the two binding sites on the regulatory subunits, which leads to the release of the catalytic subunits.


The free catalytic subunits can then catalyse the transfer of ATP terminal phosphates to protein substrates at serine, or threonine residues. This phosphorylation usually results in a change in activity of the substrate. Since PKAs are present in a variety of cells and act on different substrates, PKA and cAMP regulation are involved in many different pathways.

The mechanisms of further effects may be divided into direct protein phosphorylation and protein synthesis:

* In direct protein phosphorylation PKA directly either increases or decreases the activity of a protein.
* In protein synthesis PKA first directly activates CREB, which binds the cAMP response element, altering the transcription and therefore the synthesis of the protein. This mechanism generally takes longer time (hours to days).

PKA is thus controlled by cAMP. Also, the catalytic subunit itself can be down-regulated by phosphorylation.

Downregulation of protein kinase A occurs by a feedback mechanism: One of the substrates that is activated by the kinase is a phosphodiesterase, which quickly converts cAMP to AMP, thus reducing the amount of cAMP that can activate protein kinase A.


The 2 regulatory subunits of protein kinase A are important for localizing the kinase inside the cell, with the aid of A-kinase anchoring protein (AKAP), AKAP binds both to the regulatory subunits and to either a component of cytoskeleton structure or a membrane of an organelle, anchoring the enzyme complex to a particular subcellular compartment.

The catalytic function of protein kinase A would sometimes couple with the AKAP, binding PKA together with phosphodiesterase to form a complex that functions as a signal module. For example, an AKAP locating near the nucleus of a heart muscle cell, would bind to both PKA and phosphodiesterase that hydrolyzes cAMP. As phosphodiesterase contributes to the steady low concentration of cAMP in unstimulated cells, as the cell is stimulated, PKA is then responsible for the activation of phosphodiesterase (adjacent to PKA) in order to lower the concentration of cAMP. In this condition, as PKA and phosphodiesterase have formed a complex, the proximity increases the efficiency of PKA's activity.

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