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CAMP-dependent protein kinase

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CAMP-dependent protein kinase

CAMP-dependent protein kinase
Identifiers
EC number CAS number IntEnz BRENDA ExPASy KEGG MetaCyc metabolic pathway
PRIAM PDB structures PDBsum

In metabolism.

It should neither be confused with AMP-activated protein kinase - which, although being of similar nature, may have opposite effects -[1] nor be confused with cyclin-dependent kinases (Cdks), nor be confused with the acid dissociation constant pKa.

Mechanism


Activation

Each PKA is a holoenzyme that consists of a regulatory subunit dimer, with each regulatory subunit being bound to a catalytic subunit. 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. For maximal function, each catalytic subunit must also be phosphorylated, which occurs on Thr 197 and helps orientate catalytic residues in the active site.[2]

1. Cytosolic cAMP increases 2. Two cAMP molecules bind to each PKA regulatory subunit 3. The regulatory subunits move out of the active sites of the catalytic subunits and the R2C2 complex dissociates 4. The free catalytic subunits interact with proteins to phosphorylate Ser or Thr residues.

Catalysis

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 regulation 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. In general, this mechanism takes more time (hours to days).

Inactivation

Downregulation of protein kinase A occurs by a feedback mechanism: One of the substrates that are 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.

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

Anchorage

The regulatory subunit dimer of PKA is important for localizing the kinase inside the cell. The dimerization and docking (D/D) domain of the dimer binds to the A-kinase binding (AKB) domain of A-kinase anchor protein (AKAP). The AKAPs localize PKA to various locations (e.g., plasma membrane, mitochondria, etc.) within the cell.

AKAPs bind many other signaling proteins, creating a very efficient signaling hub at a certain location within the cell. For example, an AKAP located near the nucleus of a heart muscle cell would bind both PKA and phosphodiesterase (hydrolyzes cAMP), which allows the cell to limit the productivity of PKA, since the catalytic subunit is activated once cAMP binds to the regulatory subunits.

Function

PKA phosphorylates proteins that have the motif Arginine-Arginine-X-Serine exposed, in turn (de)activating the proteins. As protein expression varies from cell type to cell type, the proteins that are available for phosphorylation will depend upon the cell in which PKA is present. Thus, the effects of PKA activation vary with cell type:

Overview table

Cell type Organ/system Stimulators
ligands --> Gs-GPCRs
or PDE inhibitors
Inhibitors
ligands --> Gi-GPCRs
or PDE stimulators
Effects
adipocyte
myocyte (skeletal muscle) muscular system
myocyte (cardiac muscle) muscular system
hepatocyte liver
neurons in nucleus accumbens nervous system dopamine --> dopamine receptor Activate reward system
principal cells in kidney kidney
myocyte (smooth muscle) muscular system Vasodilation
Thick ascending limb cell kidney Vasopressin --> V2 receptor stimulate Na-K-2Cl symporter (perhaps only minor effect)[5]
Cortical collecting tubule cell kidney Vasopressin --> V2 receptor stimulate Epithelial sodium channel (perhaps only minor effect)[5]
Inner medullary collecting duct cell kidney Vasopressin --> V2 receptor
proximal convoluted tubule cell kidney PTH --> PTH receptor 1 Inhibit NHE3 --> ↓H+ secretion[7]
juxtaglomerular cell kidney renin secretion

In adipocytes and hepatocytes

Adrenaline and glucagon affect the activity of protein kinase A by changing the levels of cAMP in a cell via the G-protein mechanism, using adenylate cyclase. Protein Kinase A acts to phosphorylate many enzymes important in metabolism. For example, protein kinase A phosphorylates acetyl-CoA carboxylase and pyruvate dehydrogenase. Such covalent modification has an inhibitory effect on these enzymes, thus inhibiting lipogenesis and promoting net gluconeogenesis. Insulin, on the other hand, decreases the level of phosphorylation of these enzymes, which instead promotes lipogenesis. Recall that gluconeogenesis does not occur in myocytes.

In nucleus accumbens neurons

PKA helps transfer/translate the dopamine signal into cells. It has been found (postmortem) to be elevated in the brains of smokers, in the nucleus accumbens, which mediates reward and motivation: a part of the brain acted on by "virtually all" recreational drugs, as well as "in the area of the midbrain that responds to dopamine, which acts as a 'reward chemical' in smokers and former-smokers."[9]

See also

References

External links

  • Medical Subject Headings (MeSH)
  • - The Interactive Fly
  • cAMP-dependent protein kinase: PDB Molecule of the Month
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