| CAMP-dependent protein kinase |
| Identifiers |
| EC number |
2.7.11.11 |
| CAS number |
142008-29-5 |
| Databases |
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IntEnz view |
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BRENDA entry |
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| KEGG |
KEGG entry |
| MetaCyc |
metabolic pathway |
| PRIAM |
profile |
| PDB structures |
RCSB PDB PDBe PDBsum |
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proteins |
|
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.
Contents
- 1 Mechanism
- 1.1 Activation
- 1.2 Catalysis
- 1.3 Inactivation
- 1.4 Anchorage
- 2 Function
- 2.1 Overview table
- 2.2 In adipocytes and hepatocytes
- 2.3 In nucleus accumbens neurons
- 3 See also
- 4 References
- 5 External links
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]
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 |
|
- epinephrine --> β-adrenergic receptor
- glucagon --> Glucagon receptor
|
|
|
| myocyte (skeletal muscle) |
muscular system |
- epinephrine --> β-adrenergic receptor
|
|
- produce glucose
- stimulate glycogenolysis
- phosphorylate glycogen phosphorylase via phosphorylase kinase (activating it)[3]
- phosphorylate Acetyl-CoA carboxylase (inhibiting it)
- inhibit glycogenesis
- phosphorylate glycogen synthase (inhibiting it)[3]
- stimulate glycolysis
- phosphorylate phosphofructokinase 2 (stimulating it, cardiomyocytes only)
|
| myocyte (cardiac muscle) |
muscular system |
- norepinephrine --> β-adrenergic receptor
|
|
- sequester Ca2+ in sarcoplasmic reticulum
- phosphorylates phospholamban[4]
|
| hepatocyte |
liver |
- epinephrine --> β-adrenergic receptor
- glucagon --> Glucagon receptor
|
|
- produce glucose
- stimulate glycogenolysis
- phosphorylate glycogen phosphorylase (activating it)[3]
- phosphorylate Acetyl-CoA carboxylase (inhibiting it)
- inhibit glycogenesis
- phosphorylate glycogen synthase (inhibiting it)[3]
- stimulate gluconeogenesis
- phosphorylate fructose 2,6-bisphosphatase (stimulating it)
- inhibit glycolysis
- phosphorylate phosphofructokinase-2 (inactivating it)
- phosphorylate fructose 2,6-bisphosphatase (stimulate it)
- phosphorylate pyruvate kinase (inhibiting it)
|
| neurons in nucleus accumbens |
nervous system |
dopamine --> dopamine receptor |
|
Activate reward system |
| principal cells in kidney |
kidney |
- Vasopressin --> V2 receptor
- theophylline (PDE inhibitor)
|
|
- exocytosis of aquaporin 2 to apical membrane.[5]
- synthesis of aquaporin 2[5]
- phosphorylation of aquaporin 2 (stimulating it)[5]
|
| myocyte (smooth muscle) |
muscular system |
- β2 adrenergic agonists --> β-2 adrenergic receptor
- histamine --> Histamine H2 receptor
- prostacyclin --> prostacyclin receptor
- Prostaglandin D2 --> PGD2 receptor
- Prostaglandin E2 --> PGE2 receptor
- VIP --> VIP receptor
- L-Arginine --> imidazoline and α-2 receptor? (Gi-coupled)
|
- muscarinic agonists, e.g. acetylcholine --> muscarinic receptor M2
- NPY --> NPY receptor
|
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 |
|
- stimulate urea transporter 1
- urea transporter 1 exocytosis[6]
|
| proximal convoluted tubule cell |
kidney |
PTH --> PTH receptor 1 |
|
Inhibit NHE3 --> ↓H+ secretion[7] |
| juxtaglomerular cell |
kidney |
- adrenergic agonists --> β-receptor[8]
- agonists --> A2 receptor[8]
- dopamine --> dopamine receptor[8]
- glucagon --> glucagon receptor[8]
|
|
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]
- Protein kinase
- Signal transduction
- G protein-coupled receptor
- Serine/threonine-specific protein kinase
- Myosin light-chain kinase
- cAMP-dependent pathway
References[edit]
- ^ 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.
- ^ Voet, Voet & Pratt (2006). Fundamentals of Biochemistry. Wiley. Pg 492
- ^ a b c d e Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4. 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. PMID 16435604.
- ^ 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
- ^ Walter F., PhD. Boron. Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. ISBN 1-4160-2328-3. Page 844
- ^ Walter F., PhD. Boron. Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. ISBN 1-4160-2328-3. Page 852
- ^ 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]
- Cyclic AMP-Dependent Protein Kinases at the US National Library of Medicine Medical Subject Headings (MeSH)
- Drosophila cAMP-dependent protein kinase 1 - The Interactive Fly
- cAMP-dependent protein kinase: PDB Molecule of the Month
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Kinases: Serine/threonine-specific protein kinases (EC 2.7.11-12)
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Serine/threonine-specific protein kinases (EC 2.7.11.1-EC 2.7.11.20)
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Serine/threonine-specific protein kinases (EC 2.7.11.21-EC 2.7.11.30)
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| Polo kinase (EC 2.7.11.21) |
|
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| Cyclin-dependent kinase (EC 2.7.11.22) |
- CDK1
- CDK2
- CDKL2
- CDK3
- CDK4
- CDK5
- CDKL5
- CDK6
- CDK7
- CDK8
- CDK9
- CDK10
- CDC2L5
- CRKRS
- PCTK1
- PCTK2
- PCTK3
- PFTK1
- CDC2L1
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| (RNA-polymerase)-subunit kinase (EC 2.7.11.23) |
- RPS6KA5
- RPS6KA4
- P70S6 kinase
- P70-S6 Kinase 1
- RPS6KB2
- RPS6KA2
- RPS6KA3
- RPS6KA1
- RPS6KC1
|
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| Mitogen-activated protein kinase (EC 2.7.11.24) |
- Extracellular signal-regulated
- MAPK1
- MAPK3
- MAPK4
- MAPK6
- MAPK7
- MAPK12
- MAPK15
- C-Jun N-terminal
- P38 mitogen-activated protein
|
|
| MAP3K (EC 2.7.11.25) |
- MAP kinase kinase kinases
- MAP3K1
- MAP3K2
- MAP3K3
- MAP3K4
- MAP3K5
- MAP3K6
- MAP3K7
- MAP3K8
- RAFs
- MLKs
- MAP3K12
- MAP3K13
- MAP3K9
- MAP3K10
- MAP3K11
- MAP3K7
- ZAK
- CDC7
- MAP3K14
|
|
| Tau-protein kinase (EC 2.7.11.26) |
|
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| (acetyl-CoA carboxylase) kinase (EC 2.7.11.27) |
-
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| Tropomyosin kinase (EC 2.7.11.28) |
-
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| Low-density-lipoprotein receptor kinase (EC 2.7.11.29) |
-
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| Receptor protein serine/threonine kinase (EC 2.7.11.30) |
- Bone morphogenetic protein receptors
- BMPR1
- BMPR1A
- BMPR1B
- BMPR2
- ACVR1
- ACVR1B
- ACVR1C
- ACVR2A
- ACVR2B
- ACVRL1
- Anti-Müllerian hormone receptor
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Dual-specificity kinases (EC 2.7.12)
|
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| MAP2K |
- MAP2K1
- MAP2K2
- MAP2K3
- MAP2K4
- MAP2K5
- MAP2K6
- MAP2K7
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- B
- enzm
- 1.1
- 2
- 3
- 4
- 5
- 6
- 7
- 8
- 10
- 11
- 13
- 14
- 15-18
- 2.1
- 3.1
- 4.1
- 5.1
- 6.1-3
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Intracellular signaling peptides and proteins
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| MAP |
|
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| Calcium |
- Intracellular calcium-sensing proteins
- Calcineurin
- Ca2+/calmodulin-dependent protein kinase
|
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| G protein |
| Heterotrimeric |
| cAMP: |
- Heterotrimeric G protein
- Adenylate cyclase
- cAMP
- 3',5'-cyclic-AMP phosphodiesterase
- Protein kinase A
|
|
| cGMP: |
- Guanylate cyclase
- cGMP
- 3',5'-cyclic-GMP phosphodiesterase
- Protein kinase G
|
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- G beta-gamma complex Gβ
- Gγ
- GNGT1
- GNGT2
- GNG2
- GNG3
- GNG4
- GNG5
- GNG7
- GNG8
- GNG10
- GNG11
- GNG12
- GNG13
- BSCL2
|
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- G protein-coupled receptor kinase
- AMP-activated protein kinase
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| Monomeric |
- ARFs
- Rabs
- Ras
- Rhos
- Arfs
- Ran
- Rhebs
- Raps
- RGKs
|
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| Cyclin |
- Cyclin-dependent kinase inhibitor protein
- Cyclin-dependent kinase
- Cyclin
|
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| Lipid |
- Phosphoinositide phospholipase C
- Phospholipase C
|
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| Other protein kinase |
| Serine/threonine: |
- Casein kinase
- eIF-2 kinase
- Glycogen synthase kinase
- GSK1
- GSK2
- GSK-3
- GSK3A
- GSK3B
- IκB kinase
- Interleukin-1 receptor-associated kinase
- Lim kinase
- p21-activated kinases
- Rho-associated protein kinase
- Ribosomal s6 kinase
|
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| Tyrosine: |
- ZAP70
- Focal adhesion protein-tyrosine kinase
- BTK
|
|
| both |
|
|
|
| Other phosphoprotein phosphatase |
| Serine/threonine: |
|
|
| Tyrosine: |
- protein tyrosine phosphatase: Receptor-like protein tyrosine phosphatase
- Sh2 domain-containing protein tyrosine phosphatase
|
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| both: |
- Dual-specificity phosphatase
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| Apoptosis |
- see apoptosis signaling pathway
|
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| GTP-binding protein regulators |
- see GTP-binding protein regulators
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| Other |
- Activating transcription factor 6
- Signal transducing adaptor protein
- I-kappa B protein
- Mucin-4
- Olfactory marker protein
- Phosphatidylethanolamine binding protein
- EDARADD
- PRKCSH
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see also deficiencies of intracellular signaling peptides and proteins
B trdu: iter (nrpl/grfl/cytl/horl), csrc (lgic, enzr, gprc, igsr, intg, nrpr/grfr/cytr), itra (adap, gbpr, mapk), calc, lipd; path (hedp, wntp, tgfp+mapp, notp, jakp, fsap, hipp, tlrp)
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