Protein kinase A: Wikis

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protein kinase A (PKA) refers to a family of enzymes whose activity is dependent on the level of cyclic AMP (cAMP) in the cell, in cell biology. 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 is important in regulating cell cycle, along with the protein cyclin.

It should not be confused with AMP-activated protein kinase, which, although being of similar nature, may have opposite effects. [1]

Contents

Mechanism

Overview: Activation and inactivation mechanisms of PKA
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Activation

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.

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 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).

Inactivation

cAMP

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.

Anchorage

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.

Function

PKA phosphorylates other proteins, altering their function. However, which proteins are available for phosphorylation will first depend upon what kind of cell the PKA activity is present within, since protein composition varies from cell type to cell type. Thus, the effects of PKA activity varies 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) [4]
Cortical collecting tubule cell kidney Vasopressin --> V2 receptor stimulate Epithelial sodium channel (perhaps only minor effect) [4]
Inner medullary collecting duct cell kidney Vasopressin --> V2 receptor
proximal convoluted tubule cell kidney PTH --> PTH receptor 1 Inhibit NHE3 --> ↓H+ secretion[6]
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." [8]

See also

References

  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. PMID 19211918. 
  2. ^ a b c d e Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4.  Page 172
  3. ^ 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. 
  4. ^ 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
  5. ^ Walter F., PhD. Boron. Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. ISBN 1-4160-2328-3.  Page 844
  6. ^ Walter F., PhD. Boron. Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. ISBN 1-4160-2328-3.  Page 852
  7. ^ a b c d Walter F., PhD. Boron (2003). Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. pp. 1300. ISBN 1-4160-2328-3.  Page 867
  8. ^ BBC NEWS | Health | Smoking alters brain 'like drugs'

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