Structural Biochemistry/Cell Signaling Pathways/Adenylate Cyclase and cAMP Signaling

Adenylate Cyclase and cAMP Signaling
Cyclic adenine monophosphate (cAMP) is a secondary messenger used in intercellular signal transduction. The synthesis of cAMP from ATP is done by adenylyl cyclases located in the plasma membrane. The understanding of this signaling mechanism is attributed to Earl W. Sutherland whose work won him the Nobel Prize in 1971.

cAMP is used for intracellular signal transduction and affects a number of cellular processes. For example, cAMP stimulates the production of ATP for muscle contraction. In other cells, cAMP enhances the degradation of storage fuels, increases the secretion of acid by the gastric mucosa, leads to the dispersion of melanin pigment gradules, and diminishes the aggregation of blood platelets. It is also involved in the activation of protein kinases and regulates the effects of adrenaline and glucagon. In addition, cAMP regulates the passage of metal ions, like Ca2+, through ion channels.

cAMP works by activating protein kinase A (PKA). PKA is a normally inactive tetrameric holoenzyme, consisting of two catalytic and two regulatory units (C2R2), with the regulatory units blocking the catalytic centers of the catalytic units. cAMP binds to specific locations on the regulatory units of the protein kinase, and causes dissociation between the regulatory and catalytic subunits, thus activating the catalytic units and enabling them to phosphorylate substrate proteins. Binding of four cAMP molecules causes the release of free and active catalytic subunits, which may phosphorylate serine and threonine residues on target proteins. The figure below shows a cAMP/PKA signaling pathway:



The active subunits catalyze the transfer of phosphate from ATP to specific serine or threonine residues of protein substrates. The phosphorylated proteins may act directly on the cell's ion channels, or may become activated or inhibited enzymes. PKA can also phosphorylate specific proteins that bind to promoter regions of DNA, causing increased expression of specific genes.

Mechanism
When a signal is first transducted inside the cell, an enzyme called adenylyl cyclase is activated which converts ATP to cAMP. Then the cAMP activates protein kinase A by binding to the regulatory units in protein kinase A, thereby allowing the disassociation between the catalytic and regulatory subunits in protein kinase A. The newly activated protein kinase A allows for the phosphorylation of serine and threonine from ATP which generates cellular response. This secondary messenger amplifies the signal many times over through the synthesis of many molecules of cAMP by adenylyl cyclase. However, the cAMP molecules do not last long as another enzyme, phosphodiesterase, converts cAMP to AMP which means another signal is necessary in order for another response to occur.