Protein kinase A

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cAMP-dependent protein kinase (Protein kinase A)
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cAMP-dependent protein kinase hetero12mer, Sus scrofa
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EC no. 2.7.11.11
CAS no. 142008-29-5
Alt. namesSTK22, PKA, PKA C
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In cell biology, protein kinase A (PKA) is a family of serine-threonine kinase [1] 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). PKA has several functions in the cell, including regulation of glycogen, sugar, and lipid metabolism. It should not be confused with 5'-AMP-activated protein kinase (AMP-activated protein kinase).

Contents

History

Protein kinase A, more precisely known as adenosine 3',5'-monophosphate (cyclic AMP)-dependent protein kinase, abbreviated to PKA, was discovered by chemists Edmond H. Fischer and Edwin G. Krebs in 1968. They won the Nobel Prize in Physiology or Medicine in 1992 for their work on phosphorylation and dephosphorylation and how it relates to PKA activity. [2]

PKA is one of the most widely researched protein kinases, in part because of its uniqueness; out of 540 different protein kinase genes that make up the human kinome, only one other protein kinase, casein kinase 2, is known to exist in a physiological tetrameric complex, meaning it consists of four subunits. [1]

The diversity of mammalian PKA subunits was realized after Dr. Stan McKnight and others identified four possible catalytic subunit genes and four regulatory subunit genes. In 1991, Susan Taylor and colleagues crystallized the PKA Cα subunit, which revealed the bi-lobe structure of the protein kinase core for the very first time, providing a blueprint for all the other protein kinases in a genome (the kinome). [3]

Structure

When inactive, the PKA apoenzyme exists as a tetramer which consists of two regulatory subunits and two catalytic subunits. The catalytic subunit contains the active site, a series of canonical residues found in protein kinases that bind and hydrolyse ATP, and a domain to bind the regulatory subunit. The regulatory subunit has domains to bind to cyclic AMP, a domain that interacts with catalytic subunit, and an auto inhibitory domain. There are two major forms of regulatory subunit; RI and RII. [4]

Mammalian cells have at least two types of PKAs: type I is mainly in the cytosol, whereas type II is bound via its regulatory subunits and special anchoring proteins, described in the anchorage section, to the plasma membrane, nuclear membrane, mitochondrial outer membrane, and microtubules. In both types, once the catalytic subunits are freed and active, they can migrate into the nucleus (where they can phosphorylate transcription regulatory proteins), while the regulatory subunits remain in the cytoplasm. [5]

The following human genes encode PKA subunits:

Mechanism

Overview: Activation and inactivation mechanisms of PKA PKARII.svg
Overview: Activation and inactivation mechanisms of PKA

Activation

PKA is also commonly known as cAMP-dependent protein kinase, because it has traditionally been thought to be activated through release of the catalytic subunits when levels of the second messenger called cyclic adenosine monophosphate, or cAMP, rise in response to a variety of signals. However, recent studies evaluating the intact holoenzyme complexes, including regulatory AKAP-bound signalling complexes, have suggested that the local sub cellular activation of the catalytic activity of PKA might proceed without physical separation of the regulatory and catalytic components, especially at physiological concentrations of cAMP. [6] [7] In contrast, experimentally induced supra physiological concentrations of cAMP, meaning higher than normally observed in cells, are able to cause separation of the holoenzymes, and release of the catalytic subunits. [6]

Extracellular hormones, such as glucagon and epinephrine, begin an intracellular signalling cascade that triggers protein kinase A activation by first 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 in a reaction catalyzed by the GPCR 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 cAMP, directly increasing the cAMP level. Four cAMP molecules are able to bind to the two regulatory subunits. This is done by two cAMP molecules binding to each of the two cAMP binding sites (CNB-B and CNB-A) which induces a conformational change in the regulatory subunits of PKA, causing the subunits to detach and unleash the two, now activated, catalytic subunits. [8]

Once released from inhibitory regulatory subunit, the catalytic subunits can go on to phosphorylate a number of other proteins in the minimal substrate context Arg-Arg-X-Ser/Thr., [9] although they are still subject to other layers of regulation, including modulation by the heat stable pseudosubstrate inhibitor of PKA, termed PKI. [7] [10]

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 liberated 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:

Phosphorylation mechanism

The Serine/Threonine residue of the substrate peptide is orientated in such a way that the hydroxyl group faces 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 the transfer of gamma-phosphate to the Serine/Threonine of the peptide substrate. There are several conserved residues, include Glutamate (E) 91 and Lysine (K) 72, that mediate the positioning of alpha- and beta-phosphate groups. The hydroxyl group of 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 phosphodiester bond between the beta-phosphate and the gamma-phosphate groups. PKA acts as a model for understanding protein kinase biology, with the position of the conserved residues helping to distinguish the active protein kinase and inactive pseudokinase members of the human kinome.

Inactivation

cAMP CAMP.svg
cAMP

Downregulation of protein kinase A occurs by a feedback mechanism and uses a number of cAMP hydrolyzing phosphodiesterase (PDE) enzymes, which belong to the substrates activated by PKA. Phosphodiesterase quickly converts cAMP to AMP, thus reducing the amount of cAMP that can activate protein kinase A. PKA is also regulated by a complex series of phosphorylation events, which can include modification by autophosphorylation and phosphorylation by regulatory kinases, such as PDK1. [7]

Thus, PKA is controlled, in part, by the levels of 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. Many possible substrates of PKA exist; a list of such substrates is available and maintained by the NIH. [11]

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/systemStimulators
ligands → Gs-GPCRs
or PDE inhibitors 		Inhibitors
ligands → Gi-GPCRs
or PDE stimulators		Effects
adipocyte
myocyte (skeletal muscle) muscular system
myocyte (cardiac muscle) cardiovascular
myocyte (smooth muscle) cardiovascular Contributes to vasodilation (phosphorylates, and thereby inactivates, Myosin light-chain kinase)
hepatocyte liver
neurons in nucleus accumbens nervous system dopamine → dopamine receptor Activate reward system
principal cells in kidney kidney
Thick ascending limb cell kidney Vasopressin → V2 receptor stimulate Na-K-2Cl symporter (perhaps only minor effect) [14]
Cortical collecting tubule cell kidney Vasopressin → V2 receptor stimulate Epithelial sodium channel (perhaps only minor effect) [14]
Inner medullary collecting duct cell kidney Vasopressin → V2 receptor
proximal convoluted tubule cell kidney PTH → PTH receptor 1 Inhibit NHE3 → ↓H+ secretion [16]
juxtaglomerular cell kidney renin secretion

In adipocytes and hepatocytes

Epinephrine 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. Protein Kinase A signal transduction pathway helps in modulation of ethanol consumption and its sedative effects. A mouse study reports that mice with genetically reduced cAMP-PKA signalling results into less consumption of ethanol and are more sensitive to its sedative effects. [18]

In skeletal muscle

PKA is directed to specific sub-cellular locations after tethering to AKAPs. Ryanodine receptor (RyR) co-localizes with the muscle AKAP and RyR phosphorylation and efflux of Ca2+ is increased by localization of PKA at RyR by AKAPs. [19]

In cardiac muscle

In a cascade mediated by a GPCR known as β1 adrenoceptor, activated by catecholamines (notably norepinephrine), PKA gets activated and phosphorylates numerous targets, namely: L-type calcium channels, phospholamban, troponin I, myosin binding protein C, and potassium channels. This increases inotropy as well as lusitropy, increasing contraction force as well as enabling the muscles to relax faster. [20] [21]

In memory formation

PKA has always been considered important in formation of a memory. In the fruit fly, reductions in expression activity of DCO (PKA catalytic subunit encoding gene) can cause severe learning disabilities, middle term memory and short term memory. Long term memory is dependent on the CREB transcription factor, regulated by PKA. A study done on drosophila reported that an increase in PKA activity can affect short term memory. However, a decrease in PKA activity by 24% inhibited learning abilities and a decrease by 16% affected both learning ability and memory retention. Formation of a normal memory is highly sensitive to PKA levels. [22]

See also

Related Research Articles

<span class="mw-page-title-main">Cyclic adenosine monophosphate</span> Cellular second messenger

Cyclic adenosine monophosphate is a second messenger, or cellular signal occurring within cells, that is important in many biological processes. cAMP is a derivative of adenosine triphosphate (ATP) and used for intracellular signal transduction in many different organisms, conveying the cAMP-dependent pathway.

<span class="mw-page-title-main">Protein kinase</span> Enzyme that adds phosphate groups to other proteins

A protein kinase is a kinase which selectively modifies other proteins by covalently adding phosphates to them (phosphorylation) as opposed to kinases which modify lipids, carbohydrates, or other molecules. Phosphorylation usually results in a functional change of the target protein (substrate) by changing enzyme activity, cellular location, or association with other proteins. The human genome contains about 500 protein kinase genes and they constitute about 2% of all human genes. There are two main types of protein kinase. The great majority are serine/threonine kinases, which phosphorylate the hydroxyl groups of serines and threonines in their targets. Most of the others are tyrosine kinases, although additional types exist. Protein kinases are also found in bacteria and plants. Up to 30% of all human proteins may be modified by kinase activity, and kinases are known to regulate the majority of cellular pathways, especially those involved in signal transduction.

A protein phosphatase is a phosphatase enzyme that removes a phosphate group from the phosphorylated amino acid residue of its substrate protein. Protein phosphorylation is one of the most common forms of reversible protein posttranslational modification (PTM), with up to 30% of all proteins being phosphorylated at any given time. Protein kinases (PKs) are the effectors of phosphorylation and catalyse the transfer of a γ-phosphate from ATP to specific amino acids on proteins. Several hundred PKs exist in mammals and are classified into distinct super-families. Proteins are phosphorylated predominantly on Ser, Thr and Tyr residues, which account for 79.3, 16.9 and 3.8% respectively of the phosphoproteome, at least in mammals. In contrast, protein phosphatases (PPs) are the primary effectors of dephosphorylation and can be grouped into three main classes based on sequence, structure and catalytic function. The largest class of PPs is the phosphoprotein phosphatase (PPP) family comprising PP1, PP2A, PP2B, PP4, PP5, PP6 and PP7, and the protein phosphatase Mg2+- or Mn2+-dependent (PPM) family, composed primarily of PP2C. The protein Tyr phosphatase (PTP) super-family forms the second group, and the aspartate-based protein phosphatases the third. The protein pseudophosphatases form part of the larger phosphatase family, and in most cases are thought to be catalytically inert, instead functioning as phosphate-binding proteins, integrators of signalling or subcellular traps. Examples of membrane-spanning protein phosphatases containing both active (phosphatase) and inactive (pseudophosphatase) domains linked in tandem are known, conceptually similar to the kinase and pseudokinase domain polypeptide structure of the JAK pseudokinases. A complete comparative analysis of human phosphatases and pseudophosphatases has been completed by Manning and colleagues, forming a companion piece to the ground-breaking analysis of the human kinome, which encodes the complete set of ~536 human protein kinases.

<span class="mw-page-title-main">Kinase</span> Enzyme catalyzing transfer of phosphate groups onto specific substrates

In biochemistry, a kinase is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule donates a phosphate group to the substrate molecule. As a result, kinase produces a phosphorylated substrate and ADP. Conversely, it is referred to as dephosphorylation when the phosphorylated substrate donates a phosphate group and ADP gains a phosphate group. These two processes, phosphorylation and dephosphorylation, occur four times during glycolysis.

<span class="mw-page-title-main">Cyclin-dependent kinase</span> Class of enzymes

Cyclin-dependent kinases (CDKs) are a predominant group of serine/threonine protein kinases involved in the regulation of the cell cycle and its progression, ensuring the integrity and functionality of cellular machinery. These regulatory enzymes play a crucial role in the regulation of eukaryotic cell cycle and transcription, as well as DNA repair, metabolism, and epigenetic regulation, in response to several extracellular and intracellular signals. They are present in all known eukaryotes, and their regulatory function in the cell cycle has been evolutionarily conserved. The catalytic activities of CDKs are regulated by interactions with CDK inhibitors (CKIs) and regulatory subunits known as cyclins. Cyclins have no enzymatic activity themselves, but they become active once they bind to CDKs. Without cyclin, CDK is less active than in the cyclin-CDK heterodimer complex. CDKs phosphorylate proteins on serine (S) or threonine (T) residues. The specificity of CDKs for their substrates is defined by the S/T-P-X-K/R sequence, where S/T is the phosphorylation site, P is proline, X is any amino acid, and the sequence ends with lysine (K) or arginine (R). This motif ensures CDKs accurately target and modify proteins, crucial for regulating cell cycle and other functions. Deregulation of the CDK activity is linked to various pathologies, including cancer, neurodegenerative diseases, and stroke.

Maturation-promoting factor (abbreviated MPF, also called mitosis-promoting factor or M-Phase-promoting factor) is the cyclin-Cdk complex that was discovered first in frog eggs. It stimulates the mitotic and meiotic phases of the cell cycle. MPF promotes the entrance into mitosis (the M phase) from the G2 phase by phosphorylating multiple proteins needed during mitosis. MPF is activated at the end of G2 by a phosphatase, which removes an inhibitory phosphate group added earlier.

In cell biology, Protein kinase C, commonly abbreviated to PKC (EC 2.7.11.13), is a family of protein kinase enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins, or a member of this family. PKC enzymes in turn are activated by signals such as increases in the concentration of diacylglycerol (DAG) or calcium ions (Ca2+). Hence PKC enzymes play important roles in several signal transduction cascades.

cGMP-dependent protein kinase Protein kinase

cGMP-dependent protein kinase or protein kinase G (PKG) is a serine/threonine-specific protein kinase that is activated by cGMP. It phosphorylates a number of biologically important targets and is implicated in the regulation of smooth muscle relaxation, platelet function, sperm metabolism, cell division, and nucleic acid synthesis.

CAMK, also written as CaMK or CCaMK, is an abbreviation for the Ca2+/calmodulin-dependent protein kinase class of enzymes. CAMKs are activated by increases in the concentration of intracellular calcium ions (Ca2+) and calmodulin. When activated, the enzymes transfer phosphates from ATP to defined serine or threonine residues in other proteins, so they are serine/threonine-specific protein kinases. Activated CAMK is involved in the phosphorylation of transcription factors and therefore, in the regulation of expression of responding genes. CAMK also works to regulate the cell life cycle (i.e. programmed cell death), rearrangement of the cell's cytoskeletal network, and mechanisms involved in the learning and memory of an organism.

<span class="mw-page-title-main">Phosphorylase kinase</span>

Phosphorylase kinase (PhK) is a serine/threonine-specific protein kinase which activates glycogen phosphorylase to release glucose-1-phosphate from glycogen. PhK phosphorylates glycogen phosphorylase at two serine residues, triggering a conformational shift which favors the more active glycogen phosphorylase “a” form over the less active glycogen phosphorylase b.

The IκB kinase is an enzyme complex that is involved in propagating the cellular response to inflammation, specifically the regulation of lymphocytes.

<span class="mw-page-title-main">PRKACA</span> Protein-coding gene in the species Homo sapiens

The catalytic subunit α of protein kinase A is a key regulatory enzyme that in humans is encoded by the PRKACA gene. This enzyme is responsible for phosphorylating other proteins and substrates, changing their activity. Protein kinase A catalytic subunit is a member of the AGC kinase family, and contributes to the control of cellular processes that include glucose metabolism, cell division, and contextual memory. PKA Cα is part of a larger protein complex that is responsible for controlling when and where proteins are phosphorylated. Defective regulation of PKA holoenzyme activity has been linked to the progression of cardiovascular disease, certain endocrine disorders and cancers.

Polo-like kinases (Plks) are regulatory serine/threonine kinases of the cell cycle involved in mitotic entry, mitotic exit, spindle formation, cytokinesis, and meiosis. Only one Plk is found in the genomes of the fly Drosophila melanogaster (Polo), budding yeast (Cdc5) and fission yeast (Plo1). Vertebrates and other animals, however, have many Plk family members including Plk1, Plk2/Snk, Plk3/Prk/FnK, Plk4/Sak and Plk5. Of the vertebrate Plk family members, the mammalian Plk1 has been most extensively studied. During mitosis and cytokinesis, Plks associate with several structures including the centrosome, kinetochores, and the central spindle.

<span class="mw-page-title-main">BRAF (gene)</span> Protein-coding gene in the species Homo sapiens

BRAF is a human gene that encodes a protein called B-Raf. The gene is also referred to as proto-oncogene B-Raf and v-Raf murine sarcoma viral oncogene homolog B, while the protein is more formally known as serine/threonine-protein kinase B-Raf.

<span class="mw-page-title-main">Myosin-light-chain phosphatase</span>

Myosin light-chain phosphatase, also called myosin phosphatase (EC 3.1.3.53; systematic name [myosin-light-chain]-phosphate phosphohydrolase), is an enzyme (specifically a serine/threonine-specific protein phosphatase) that dephosphorylates the regulatory light chain of myosin II:

<span class="mw-page-title-main">PRKAR2A</span> Protein-coding gene in the species Homo sapiens

cAMP-dependent protein kinase type II-alpha regulatory subunit is an enzyme that in humans is encoded by the PRKAR2A gene.

<span class="mw-page-title-main">PRKACB</span> Protein-coding gene in the species Homo sapiens

cAMP-dependent protein kinase catalytic subunit beta is an enzyme that in humans is encoded by the PRKACB gene.

In the field of molecular biology, the cAMP-dependent pathway, also known as the adenylyl cyclase pathway, is a G protein-coupled receptor-triggered signaling cascade used in cell communication.

The Akt signaling pathway or PI3K-Akt signaling pathway is a signal transduction pathway that promotes survival and growth in response to extracellular signals. Key proteins involved are PI3K and Akt.

<span class="mw-page-title-main">Autophosphorylation</span>

Autophosphorylation is a type of post-translational modification of proteins. It is generally defined as the phosphorylation of the kinase by itself. In eukaryotes, this process occurs by the addition of a phosphate group to serine, threonine or tyrosine residues within protein kinases, normally to regulate the catalytic activity. Autophosphorylation may occur when a kinases' own active site catalyzes the phosphorylation reaction, or when another kinase of the same type provides the active site that carries out the chemistry. The latter often occurs when kinase molecules dimerize. In general, the phosphate groups introduced are gamma phosphates from nucleoside triphosphates, most commonly ATP.

References

  1. 1 2 Turnham, Rigney E.; Scott, John D. (2016-02-15). "Protein kinase A catalytic subunit isoform PRKACA; History, function and physiology". Gene. 577 (2): 101–108. doi:10.1016/j.gene.2015.11.052. PMC   4713328 . PMID   26687711.
  2. ↑ Knighton, D. R.; Zheng, J. H.; Ten Eyck, L. F.; Xuong, N. H.; Taylor, S. S.; Sowadski, J. M. (1991-07-26). "Structure of a peptide inhibitor bound to the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase". Science. 253 (5018): 414–420. Bibcode:1991Sci...253..414K. doi:10.1126/science.1862343. ISSN   0036-8075. PMID   1862343.
  3. ↑ Manning, G.; Whyte, D. B.; Martinez, R.; Hunter, T.; Sudarsanam, S. (2002-12-06). "The protein kinase complement of the human genome". Science. 298 (5600): 1912–1934. Bibcode:2002Sci...298.1912M. doi:10.1126/science.1075762. ISSN   1095-9203. PMID   12471243. S2CID   26554314.
  4. ↑ Bauman AL, Scott JD (August 2002). "Kinase- and phosphatase-anchoring proteins: harnessing the dynamic duo". Nature Cell Biology. 4 (8): E203–6. doi:10.1038/ncb0802-e203. PMID   12149635. S2CID   1276537.
  5. ↑ Alberts, Bruce (18 November 2014). Molecular biology of the cell (Sixth ed.). New York. p. 835. ISBN   978-0-8153-4432-2. OCLC   887605755.{{cite book}}: CS1 maint: location missing publisher (link)
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  7. 1 2 3 Byrne, DP; Vonderach, M; Ferries, S; Brownridge, PJ; Eyers, CE; Eyers, PA (2016). "cAMP-dependent protein kinase (PKA) complexes probed by complementary differential scanning fluorimetry and ion mobility-mass spectrometry". Biochemical Journal. 473 (19): 3159–3175. doi:10.1042/bcj20160648. PMC   5095912 . PMID   27444646.
  8. ↑ Lodish; et al. (2016). "15.5". Molecular Cell Biology (8th ed.). W.H. Freeman and Company. p. 701. ISBN   978-1-4641-8339-3.
  9. ↑ Voet, Voet & Pratt (2008). Fundamentals of Biochemistry, 3rd Edition. Wiley. Pg 432
  10. ↑ Scott, JD; Glaccum, MB; Fischer, EH; Krebs, EG (1986). "Primary-structure requirements for inhibition by the heat-stable inhibitor of the cAMP-dependent protein kinase". PNAS. 83 (6): 1613–1616. Bibcode:1986PNAS...83.1613S. doi: 10.1073/pnas.83.6.1613 . PMC   323133 . PMID   3456605.
  11. ↑ "PKA Substrates". NIH.
  12. 1 2 3 4 5 Rang HP (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN   978-0-443-07145-4. Page 172
  13. ↑ Rodriguez P, Kranias EG (December 2005). "Phospholamban: a key determinant of cardiac function and dysfunction". Archives des Maladies du Coeur et des Vaisseaux. 98 (12): 1239–43. PMID   16435604.
  14. 1 2 3 4 5 Boron WF, Boulpaep EL (2005). Medical Physiology: A Cellular And Molecular Approach (Updated ed.). Philadelphia, Pa.: Elsevier Saunders. p. 842. ISBN   978-1-4160-2328-9.
  15. ↑ Boron WF, Boulpaep EL (2005). Medical Physiology: A Cellular And Molecular Approaoch (Updated ed.). Philadelphia, Pa.: Elsevier Saunders. p. 844. ISBN   978-1-4160-2328-9.
  16. ↑ Boron WF, Boulpaep EL (2005). Medical Physiology: A Cellular And Molecular Approach (Updated ed.). Philadelphia, Pa.: Elsevier Saunders. p. 852. ISBN   978-1-4160-2328-9.
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  19. ↑ Ruehr, Mary L.; Russell, Mary A.; Ferguson, Donald G.; Bhat, Manju; Ma, Jianjie; Damron, Derek S.; Scott, John D.; Bond, Meredith (2003-07-04). "Targeting of Protein Kinase A by Muscle A Kinase-anchoring Protein (mAKAP) Regulates Phosphorylation and Function of the Skeletal Muscle Ryanodine Receptor". Journal of Biological Chemistry. 278 (27): 24831–24836. doi: 10.1074/jbc.M213279200 . ISSN   0021-9258. PMID   12709444.
  20. ↑ Shah, Ajay M.; Solaro, R. John; Layland, Joanne (2005-04-01). "Regulation of cardiac contractile function by troponin I phosphorylation". Cardiovascular Research. 66 (1): 12–21. doi: 10.1016/j.cardiores.2004.12.022 . ISSN   0008-6363. PMID   15769444.
  21. ↑ Boron, Walter F.; Boulpaep, Emile L. (2012). Medical physiology : a cellular and molecular approach. Boron, Walter F.,, Boulpaep, Emile L. (Updated second ed.). Philadelphia, PA. ISBN   9781437717532. OCLC   756281854.{{cite book}}: CS1 maint: location missing publisher (link)
  22. ↑ Horiuchi, Junjiro; Yamazaki, Daisuke; Naganos, Shintaro; Aigaki, Toshiro; Saitoe, Minoru (2008-12-30). "Protein kinase A inhibits a consolidated form of memory in Drosophila". Proceedings of the National Academy of Sciences. 105 (52): 20976–20981. Bibcode:2008PNAS..10520976H. doi: 10.1073/pnas.0810119105 . ISSN   0027-8424. PMC   2634933 . PMID   19075226.

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