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- The title of this article should be cAMP-dependent protein kinase. The initial letter is capitalized due to technical restrictions.
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 18.104.22.168). Protein kinase A has several functions in the cell, including regulation of glycogen, sugar, and lipid metabolism.
It should be confused neither with AMP-activated protein kinase - which, although being of similar nature, may have opposite effects - nor with cyclin-dependent kinases (Cdks), nor with the acid dissociation constant pKa.
Mechanism[edit | edit source]
Activation[edit | edit source]
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.
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 | edit source]
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 | edit source]
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 | edit source]
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 | edit source]
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 | edit source]
In adipocytes and hepatocytes[edit | edit source]
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 | edit source]
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."
See also[edit | edit source]
- Protein kinase
- Signal transduction
- G protein-coupled receptor
- Serine/threonine-specific protein kinase
- Myosin light-chain kinase
- cAMP-dependent pathway
References[edit | edit source]
- 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.
- Voet, Voet & Pratt (2006). Fundamentals of Biochemistry. Wiley. Pg 492
- Rang, H. P. (2003). Pharmacology, Edinburgh: Churchill Livingstone. Page 172
- Rodriguez P, Kranias EG. (December 2005). Phospholamban: a key determinant of cardiac function and dysfunction.. Arch Mal Coeur Vaiss 98 (12): 1239–43.
- Walter F., PhD. Boron. Medical Physiology: A Cellular And Molecular Approaoch, Elsevier/Saunders. Page 842 Cite error: Invalid
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- Walter F., PhD. Boron. Medical Physiology: A Cellular And Molecular Approaoch, Elsevier/Saunders. Page 844
- Walter F., PhD. Boron. Medical Physiology: A Cellular And Molecular Approaoch, Elsevier/Saunders. Page 852
- Walter F., PhD. Boron (2003). Medical Physiology: A Cellular And Molecular Approaoch, 1300, Elsevier/Saunders. Page 867
- includeonly>"Smoking alters brain 'like drugs'", BBC News, 2007-02-24. Retrieved on 2010-05-22.
[edit | edit source]
- de:Proteinkinase A
Kinases: Serine/threonine-specific protein kinases (primarily EC 2.7.11)
Pyruvate dehydrogenase kinase - Protein kinase A - Protein kinase G - Protein kinase C (Protein kinase Mζ) - Rhodopsin - Beta adrenergic receptor - G-protein coupled receptor kinases - Ca2+/calmodulin-dependent - Myosin light-chain) - Phosphorylase - Cyclin-dependent - Mitogen-activated (Extracellular signal-regulated, C-Jun N-terminal, P38 mitogen-activated protein) - MAP3K - GSK-3 - AMP-activated
|22.214.171.124, or unknown||
Anti-Mullerian hormone receptor - Ataxia telangiectasia mutated - Aurora (A, B) - Mammalian target of rapamycin - Bone morphogenetic protein receptors (1, 2) - CDKL5 - c-Raf - EIF-2 - Ribosomal s6 - Protein kinase B - PDK1