Protein kinase A

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CAMP-dependent protein kinase
Identifiers
EC number 2.7.11.11
CAS number 142008-29-5
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum

In cell biology, Protein kinase A (PKA) is a family of enzymes whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase (EC 2.7.11.11). Protein kinase A has several functions in the cell, including regulation of glycogen, sugar, and lipid 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[edit]

Overview: Activation and inactivation mechanisms of PKA

Activation[edit]

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 orient 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[edit]

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[edit]

cAMP

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[edit]

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[edit]

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[edit]

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[edit]

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[edit]

PKA helps transfer/translate the dopamine signal into cells. In the nucleus accumbens, which mediates reward, motivation, and task salience. The vast majority of reward perception involves neuronal activation in the nucleus accumbens, some examples of which include sex, recreational drugs, and food.

See also[edit]

References[edit]

  1. ^ Hallows KR, Alzamora R, Li H, et al. (April 2009). "AMP-activated protein kinase inhibits alkaline pH- and PKA-induced apical vacuolar H+-ATPase accumulation in epididymal clear cells". Am. J. Physiol., Cell Physiol. 296 (4): C672–81. doi:10.1152/ajpcell.00004.2009. PMC 2670645. PMID 19211918. 
  2. ^ Voet, Voet & Pratt (2006). Fundamentals of Biochemistry. Wiley. Pg 492
  3. ^ a b c d e Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4.  Page 172
  4. ^ Rodriguez P, Kranias EG. (December 2005). "Phospholamban: a key determinant of cardiac function and dysfunction.". Arch Mal Coeur Vaiss 98 (12): 1239–43. PMID 16435604. 
  5. ^ a b c d e Walter F., PhD. Boron. Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. ISBN 1-4160-2328-3.  Page 842
  6. ^ Walter F., PhD. Boron. Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. ISBN 1-4160-2328-3.  Page 844
  7. ^ Walter F., PhD. Boron. Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. ISBN 1-4160-2328-3.  Page 852
  8. ^ a b c d Walter F., PhD. Boron (2003). Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. p. 1300. ISBN 1-4160-2328-3.  Page 867

External links[edit]