cAMP-dependent protein kinase

• サイクリックAMP依存性タンパク質キナーゼ、サイクリックAMP依存性タンパク質リン酸化酵素、cAMP依存性タンパク質リン酸化酵素

関

A-kinase、cyclic AMP-dependent protein kinase、PKA、protein kinase A

WordNet

1. give an artificially banal or sexual quality to
2. temporary living quarters specially built by the army for soldiers; "wherever he went in the camp the men were grumbling" (同)encampment, cantonment, bivouac
3. shelter for persons displaced by war or political oppression or for religious beliefs (同)refugee camp
4. a site where care and activities are provided for children during the summer months; "city kids get to see the country at a summer camp" (同)summer camp
5. a penal institution (often for forced labor); "China has many camps for political prisoners"
6. temporary lodgings in the country for travelers or vacationers; "level ground is best for parking and camp areas"
7. a group of people living together in a camp; "the whole camp laughed at his mistake"
8. something that is considered amusing not because of its originality but because of its unoriginality; "the living room was pure camp"
9. establish or set up a camp (同)camp down
10. providing sophisticated amusement by virtue of having artificially (and vulgarly) mannered or banal or sentimental qualities; "they played up the silliness of their roles for camp effect"; "campy Hollywood musicals of the 1940s" (同)campy
11. live in or as if in a tent; "Can we go camping again this summer?"; "The circus tented near the town"; "The houseguests had to camp in the living room" (同)encamp, camp out, bivouac, tent
12. relying on or requiring a person or thing for support, supply, or what is needed; "dependent children"; "dependent on moisture"
13. addicted to a drug (同)dependant, drug-addicted, hooked, strung-out
14. contingent on something else (同)dependant, qualified
15. (of a clause) unable to stand alone syntactically as a complete sentence; "a subordinate (or dependent) clause functions as a noun or adjective or adverb within a sentence" (同)subordinate
16. any of a large group of nitrogenous organic compounds that are essential constituents of living cells; consist of polymers of amino acids; essential in the diet of animals for growth and for repair of tissues; can be obtained from meat and eggs and milk and legumes; "a diet high in protein"
17. an enzyme that catalyzes the conversion of a proenzyme to an active enzyme

PrepTutorEJDIC

1. 〈C〉(軍隊・登山隊・探検隊などの)『野営地』 / 〈C〉〈U〉野営のテント,仮設小屋 / 〈U〉野営,キャンプ[生活];軍隊生活 / 〈C〉夏季キャンプ場,サマーキャンプ / 《集合的に》野営する人たち,キャンプする人たち / 〈C〉(主義・信条などを同じくする)同志たち,同じ陣営;同じ立場 / 『野営する』,キャンプ生活を送る《+『out』》
2. =homosexual / (男性が)女々しい / すたれた,古めかしい
3. 『頼っている』,依存している,従属している / 扶養される人(家族)
4. 蛋白(たんばく)質

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/05/18 12:54:44」(JST)

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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
Search PMC articles PubMed articles NCBI 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 not be confused with AMP-activated protein kinase – which, although being of similar nature, may have opposite effects – nor be confused with cyclin-dependent kinases (Cdks), nor be confused with the acid dissociation constant pKa.

Mechanism

Overview: Activation and inactivation mechanisms of PKA

Activation

The PKA enzyme is also known as cAMP-dependent enzyme because it is activated only when cAMP is present. Hormones such as glucagon and epinephrine begin the activation cascade (that triggers protein kinase A) by binding to a G protein–coupled receptor (GPCR) on the target cell. When a GPCR is activated by its extracellular ligand, a conformational change is induced in the receptor that is transmitted to an attached intracellular heterotrimeric G protein complex by protein domain dynamics. The Gs alpha subunit of the stimulated G protein complex exchanges GDP for GTP and is released from the complex. The activated Gs alpha subunit binds to and activates an enzyme called adenylyl cyclase, which, in turn, catalyzes the conversion of ATP into cyclic adenosine monophosphate (cAMP) – increasing cAMP levels. Four cAMP molecules are required to activate a single PKA enzyme. This is done by two cAMP molecules binding to each of the two regulatory subunits on a PKA enzyme causing the subunits to detach exposing the two (now activated) catalytic subunits. Next the catalytic subunits can go on to phosphorylate other proteins.

Below is a list of the steps involved in PKA activation:

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 catalyze 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).

Phosphorylation mechanism

The Serine/Threonine residue of the substrate peptide is orientated in such a way that the hydroxyl group faces towards the gamma phosphate group of the bound ATP molecule. Both the substrate, ATP, and two Mg2+ ions form intensive contacts with the catalytic subunit of PKA. In the active conformation, the C helix packs against the N-terminal lobe and the Aspartate residue of the conserved DFG motif chelates the Mg2+ ions, assisting in positioning the ATP substrate. The triphosphate group of ATP points out of the adenosine pocket for transfer of gamma-phosphate to the Serine/Threonine of the peptide substrate. There are two conserved residues, Glutamate 91 and Lysine 72, that mediate the positioning of alpha- and beta-phosphate groups. The hydroxyl group the peptide substrate's Serine/Threonine attacks the gamma phosphate group at the phosphorus via an SN2 nucleophilic reaction, which results in the transfer of the terminal phosphate to the peptide substrate and cleavage of the phosphodiesterbond between the beta-phosphate and the gamma-phosphate groups.

Inactivation

cAMP

Downregulation of protein kinase A occurs by a feedback mechanism using phosphodiesterase, which is one of the substrates activated by the kinase. Phosphodiesterase 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		epinephrine --> β-adrenergic receptor glucagon --> Glucagon receptor		enhance lipolysis stimulate lipase
myocyte (skeletal muscle)	muscular system	epinephrine --> β-adrenergic receptor		produce glucose stimulate glycogenolysis phosphorylate glycogen phosphorylase via phosphorylase kinase (activating it) phosphorylate Acetyl-CoA carboxylase (inhibiting it) inhibit glycogenesis phosphorylate glycogen synthase (inhibiting it) stimulate glycolysis phosphorylate phosphofructokinase 2 (stimulating it, cardiomyocytes only)
myocyte (cardiac muscle)	cardiovascular	norepinephrine --> β-adrenergic receptor		sequester Ca2+ in sarcoplasmic reticulum phosphorylates phospholamban
myocyte (smooth muscle)	cardiovascular	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 α2 receptor? (Gi-coupled)	muscarinic agonists, e.g. acetylcholine --> muscarinic receptor M2 NPY --> NPY receptor	Vasodilation
hepatocyte	liver	epinephrine --> β-adrenergic receptor glucagon --> Glucagon receptor		produce glucose stimulate glycogenolysis phosphorylate glycogen phosphorylase (activating it) phosphorylate Acetyl-CoA carboxylase (inhibiting it) inhibit glycogenesis phosphorylate glycogen synthase (inhibiting it) 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. synthesis of aquaporin 2 phosphorylation of aquaporin 2 (stimulating it)
Thick ascending limb cell	kidney	Vasopressin --> V2 receptor		stimulate Na-K-2Cl symporter (perhaps only minor effect)
Cortical collecting tubule cell	kidney	Vasopressin --> V2 receptor		stimulate Epithelial sodium channel (perhaps only minor effect)
Inner medullary collecting duct cell	kidney	Vasopressin --> V2 receptor		stimulate urea transporter 1 urea transporter 1 exocytosis
proximal convoluted tubule cell	kidney	PTH --> PTH receptor 1		Inhibit NHE3 --> ↓H+ secretion
juxtaglomerular cell	kidney	adrenergic agonists --> β-receptor agonists --> α2 receptor dopamine --> dopamine receptor glucagon --> glucagon receptor		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 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

• Protein kinase
• Signal transduction
• G protein-coupled receptor
• Serine/threonine-specific protein kinase
• Myosin light-chain kinase
• cAMP-dependent pathway

References

External links

• 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

Notes

UpToDate Contents

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• 1. T細胞陰性、B細胞陰性、NK細胞陽性の重度複合型免疫不全 t cell negative b cell negative nk cell positive severe combined immunodeficiency
• 2. 重度複合型免疫不全（SCID）：特定の欠損 severe combined immunodeficiency scid specific defects
• 3. 免疫不全症を引き起こすCD3／T細胞受容体複合体疾患 cd3 t cell receptor complex disorders causing immunodeficiency
• 4. ホームシック homesickness
• 5. 学校やキャンプでの食物アレルギー food allergy in schools and camps

English Journal

• Caffeine stimulates locomotor activity in the mammalian spinal cord via adenosine A1 receptor-dopamine D1 receptor interaction and PKA-dependent mechanisms.

• Acevedo J1, Santana-Almansa A1, Matos-Vergara N1, Marrero-Cordero LR1, Cabezas-Bou E1, Díaz-Ríos M2.
• Neuropharmacology.Neuropharmacology.2016 Feb;101:490-505. doi: 10.1016/j.neuropharm.2015.10.020. Epub 2015 Oct 19.
• Caffeine is a potent psychostimulant that can have significant and widely variable effects on the activity of multiple neuronal pathways. The most pronounced caffeine-induced behavioral effect seen in rodents is to increase locomotor activity which has been linked to a dose-dependent inhibition of A
• PMID 26493631

• Role of phosphodiesterase-4 on ethanol elicited locomotion and narcosis.

• Baliño P1, Ledesma JC2, Aragon CM3.
• Neuropharmacology.Neuropharmacology.2016 Feb;101:271-8. doi: 10.1016/j.neuropharm.2015.10.001. Epub 2015 Oct 9.
• The cAMP signaling pathway has emerged as an important modulator of the pharmacological effects of ethanol. In this respect, the cAMP-dependent protein kinase has been shown to play an important role in the modulation of several ethanol-induced behavioral actions. Cellular levels of cAMP are maintai
• PMID 26449868

• Effects of ketamine administration on the phosphorylation levels of CREB and TrKB and on oxidative damage after infusion of MEK inhibitor.

• Réus GZ1, Abaleira HM2, Titus SE2, Arent CO3, Michels M4, da Luz JR3, Dos Santos MA3, Carlessi AS3, Matias BI3, Bruchchen L3, Steckert AV3, Ceretta LB5, Dal-Pizzol F4, Quevedo J6.
• Pharmacological reports : PR.Pharmacol Rep.2016 Feb;68(1):177-84. doi: 10.1016/j.pharep.2015.08.010. Epub 2015 Aug 28.
• BACKGROUND: Ketamine, an antagonist of N-methyl-d-aspartate (NMDA) receptors, has presented antidepressant effects in basic and clinical studies. The MAPK kinase (MEK) signaling pathway could be a target for novel antidepressant drugs and an important pathway involved in neuronal plasticity. Thus, t
• PMID 26721370

Japanese Journal

• プロスタグランディンE_2-Epacシグナルによるラット動脈管の内膜肥厚形成の促進作用(2009年度受賞者,粟山煕賞受賞講演,第52回日本平滑筋学会総会)

• 横山 詩子,南沢 享,石川 義弘
• 日本平滑筋学会雑誌 14(1), "J-4", 2010-06-11
• NAID 110007643164

• Dipyridamole Suppresses High Glucose-Induced Osteopontin Secretion and mRNA Expression in Rat Aortic Smooth Muscle Cells

• HSIEH Ming-Song,ZHONG Wen-Bin,YU Shu-Chuan,LIN John Yi-Chung,CHI Wei-Ming,LEE Horng-Mo
• Circulation journal : official journal of the Japanese Circulation Society 74(6), 1242-1250, 2010-05-25
• … Methods and Results: The incubation of rat aortic smooth muscle cells under high glucose concentration increased osteopontin protein secretion and mRNA expression. … Dipyridamole decreased glucose-induced osteopontin through inhibition of phosphodiesterase, thereby increasing intracellular levels of adenosine-3,5-cyclic monophosphate (cAMP) and guanosine-3,5-cyclic monophosphate (cGMP), and increased thioredoxin expression to inhibit the reactive oxygen species (ROS) system. …
• NAID 10026475114

Related Links

• PDB-101: cAMP-dependent Protein Kinase (PKA)

References D. A. Johnson, P. Akamine, E. Radzio-Andzelm, Madhusudan & S. S. Taylor (2001) Dynamics of cAMP-dependent protein kinase. Chemical Reviews 101, 2243-2270. S. S. Taylor, C. Kim, D. Vigil, N. M. Haste, J. Yang ...

• cAMP-Dependent Protein Kinase, Catalytic Subunit

この精製された40kDaのcAMP-Dependent Protein Kinase(PKA),Catalytic Subunitは 標的タンパク質のリン酸化や、in vitroでの神経性およびホルモン性シグナル伝達における酵素学的研究に使用されます。細胞内の標的として、イオン ...

Related Pictures

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★リンクテーブル★

リンク元	「サイクリックAMP依存性タンパク質キナーゼ」「サイクリックAMP依存性タンパク質リン酸化酵素」「PKA」「A-kinase」「cAMP依存性タンパク質リン酸化酵素」
関連記事	「dependent」「cAMP」「kinase」「CAMP」「protein kinase」

「サイクリックAMP依存性タンパク質キナーゼ」

　　[★]

英

cyclic AMP-dependent protein kinase、cAMP-dependent protein kinase、protein kinase A、PKA

関

プロテインキナーゼA、サイクリックAMP依存性タンパク質リン酸化酵素、cAMP依存性タンパク質リン酸化酵素、サイクリックAMP依存性プロテインキナーゼ

「サイクリックAMP依存性タンパク質リン酸化酵素」

　　[★]

英

cAMP-dependent protein kinase、protein kinase A、A-kinase

関

Aキナーゼ、プロテインキナーゼA、cAMP依存性タンパク質リン酸化酵素、サイクリックAMP依存性タンパク質キナーゼ、サイクリックAMP依存性プロテインキナーゼ

「PKA」

　　[★]

• プロテインキナーゼA、サイクリックAMP依存性タンパク質キナーゼ

関

A-kinase、cAMP-dependent protein kinase、cyclic AMP-dependent protein kinase、protein kinase A

関

See Protein kinase A

関

Protein kinase A

「A-kinase」

　　[★]

Aキナーゼ、プロテインキナーゼA、サイクリックAMP依存性タンパク質リン酸化酵素

関

cAMP-dependent protein kinase、PKA、protein kinase A

「cAMP依存性タンパク質リン酸化酵素」

　　[★]

英

cAMP-dependent protein kinase

関

サイクリックAMP依存性タンパク質リン酸化酵素、サイクリックAMP依存性タンパク質キナーゼ

「dependent」

　　[★]

• adj.

• 依存性の、依存的な、依存型の、依存の

関

depend、dependence、dependency、dependently

　 　 　 　 　

「cAMP」

　　[★] 環状アデノシン一リン酸 サイクリックAMP 環状AMP adenosine 3',5'-cyclic monophosphate, cyclic AMP

「kinase」

　　[★] キナーゼ カイネース リン酸化酵素 phosphoenzyme phosphotransferase 　

「CAMP」

　　[★]

• Childhood Asthma Management Program
• 環状アデノシン一リン酸 cAMP cyclic AMP

「protein kinase」

　　[★] プロテインキナーゼ

同

protein kinases