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38-477: EPAC may refer to: rap guanine nucleotide exchange factor 3 ( RAPGEF3 ), also known as exchange factor directly activated by cAMP 1 (EPAC1) or cAMP-regulated guanine nucleotide exchange factor Electrically Power Assisted Cycle, a term used in EU regulations for Electric bicycles Eastern Pacific Ocean Hurricane basin École Pointe-au-Chien Topics referred to by
76-422: A database search for proteins with sequence homology to both GEFs for Ras and Rap1 and to cAMP-binding sites, which led to the identification and subsequent cloning of RAPGEF3 gene. The discovery of EPAC family cAMP sensors suggests that the complexity and possible readouts of cAMP signaling are much more elaborate than previously envisioned. This is due to the fact that the net physiological effects of cAMP entail
114-471: A domain that interacts with catalytic subunit, and an auto inhibitory domain. There are two major forms of regulatory subunit; RI and RII. 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
152-450: A research milestone that allows the pharmacological manipulation of EPAC activity. In particular, one EPAC antagonist , ESI-09, with excellent activity and minimal toxicity in vivo, has been shown to be a useful pharmacological tool for probing physiological functions of EPAC proteins and for testing therapeutic potential of targeting EPAC in animal disease models. Protein kinase A In cell biology , protein kinase A ( PKA )
190-527: Is a protein that in humans is encoded by the RAPGEF3 gene . As the name suggests, EPAC proteins (EPAC1 and EPAC2 ) are a family of intracellular sensors for cAMP , and function as nucleotide exchange factors for the Rap subfamily of RAS -like small GTPases . Since the landmark discovery of the prototypic second messenger cAMP in 1957, three families of eukaryotic cAMP receptors have been identified to mediate
228-527: Is a family of serine-threonine kinase 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 ). Protein kinase A, more precisely known as adenosine 3',5'-monophosphate (cyclic AMP)-dependent protein kinase, abbreviated to PKA,
266-501: Is controlled, in part, by the levels of cAMP . Also, the catalytic subunit itself can be down-regulated by phosphorylation. 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
304-609: Is different from Wikidata All article disambiguation pages All disambiguation pages RAPGEF3 223864 ENSG00000079337 ENSMUSG00000022469 O95398 Q8VCC8 NM_001098531 NM_001098532 NM_006105 NM_001177810 NM_001177811 NM_144850 NM_001357630 NP_001092001 NP_001092002 NP_006096 NP_001171281 NP_001171282 NP_659099 NP_001344559 Rap guanine nucleotide exchange factor 3 also known as exchange factor directly activated by cAMP 1 (EPAC1) or cAMP-regulated guanine nucleotide exchange factor I (cAMP-GEFI)
342-632: 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 Ca is increased by localization of PKA at RyR by AKAPs. In a cascade mediated by a GPCR known as β 1 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
380-457: Is known to exist in a physiological tetrameric complex, meaning it consists of four subunits. 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
418-428: Is localized to various subcellular locations during different stages of the cell cycle. Through interactions with an array of cellular partners, EPAC1 has been shown to form discrete signalsomes at plasma membrane, nuclear-envelope, and cytoskeleton, where EPAC1 regulates numerous cellular functions. Studies based on genetically engineered mouse models of EPAC1 have provided valuable insights into understanding
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#1733085870075456-478: Is not present in mature platelets, but is required for normal megakaryopoiesis and the subsequent expression of several important proteins involved in key platelets functions. There have been significant interests in discovering and developing small modulators specific for EPAC proteins for better understanding the functions of EPAC mediated cAMP signaling, as well as for exploring the therapeutic potential of targeting EPAC proteins. Structure-based design targeting
494-542: Is rather ubiquitous. As per Human Protein Atlas documentation, EPAC1 mRNA is detectable in all normal human tissues. Further, medium to high levels of corresponding protein are also measureable in more than 50% of the 80 tissue samples analyzed. In mice, high levels of EPAC1 mRNA are detected in kidney, ovary, skeletal muscle, thyroid and certain areas of the brain. EPAC1 is a multifunctional protein whose cellular functions are tightly regulated in spatial and temporal manners. EPAC1
532-623: 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. In contrast, experimentally induced supra physiological concentrations of cAMP, meaning higher than normally observed in cells, are able to cause separation of
570-522: 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
608-491: The EPAC protein family contains two members: EPAC1 (this protein) and EPAC2 ( RAPGEF4 ). They further belong to a more extended family of Rap/Ras-specific GEF proteins that also include C3G ( RAPGEF1 ), PDZ-GEF1 ( RAPGEF2 ), PDZ-GEF2 ( RAPGEF6 ), Repac ( RAPGEF5 ), CalDAG-GEF1 ( ARHGEF1 ), CalDAG-GEF3 ( ARHGEF3 ), PLCε1 ( PLCE1 ) and RasGEF1A , B , C . EPAC proteins consist of two structural lobes/halves connected by
646-507: 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
684-431: 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. The following human genes encode PKA subunits: 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
722-445: 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. PKA phosphorylates proteins that have
760-706: The heat stable pseudosubstrate inhibitor of PKA, termed PKI. Below is a list of the steps involved in PKA activation: 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: The Serine/Threonine residue of
798-529: The holoenzymes, and release of the catalytic subunits. 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
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#1733085870075836-517: The human kinome. 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. Thus, PKA
874-919: The in vivo functions of EPAC1 under both physiological and pathophysiological conditions. Overall, mice deficient of EPAC1 or both EPAC1 and EPAC2 appear relatively normal without major phenotypic defects. These observations are consistent with the fact that cAMP is a major stress response signal not essential for survival. This makes EPAC1 an attractive target for therapeutic intervention as the on-target toxicity of EPAC-based therapeutics will likely be low. Up to date, genetic and pharmacological analyses of EPAC1 in mice have revealed that EPAC1 plays important roles in cardiac stresses and heart failure , leptin resistance and energy homeostasis , chronic pain , infection , cancer metastasis , metabolism and secondary hemostasis . Interestingly, EPAC1 deficient mice have prolonged clotting time and fewer, younger, larger and more agonist-responsive blood platelets . EPAC1
912-600: The integration of EPAC- and PKA-dependent pathways, which may act independently, converge synergistically, or oppose each other in regulating a specific cellular function. Human RAPGEF3 gene is present on chromosome 12 (12q13.11: 47,734,367-47,771,041). Out of the many predicted transcript variants , three that are validated in the NCBI database include transcript variant 1 (6,239 bp), 2 (5,773 bp) and 3 (6,003 bp). While variant 1 encodes for EPAC1a (923 amino acids), both variant 2 and 3 encode EPAC1b (881 amino acids). In mammals,
950-499: The intracellular functions of cAMP. While protein kinase A (PKA) or cAMP-dependent protein kinase and cyclic nucleotide regulated ion channel ( CNG and HCN ) were initially unveiled in 1968 and 1985 respectively; EPAC genes were discovered in 1998 independently by two research groups. Kawasaki et al. identified cAMP-GEFI and cAMP-GEFII as novel genes enriched in brain using a differential display protocol and by screening clones with cAMP-binding motif. De Rooij and colleagues performed
988-668: The key difference between the cAMP binding sites of EPAC and PKA led to the identification of a cAMP analogue, 8-pCPT-2’-O-Me-cAMP that is capable of selectively activate EPAC1. Further modifications allowed the development of more membrane permeable and metabolically stable EPAC-specific agonists . A high throughput screening effort resulted in the discovery of several novel EPAC specific inhibitors (ESIs), among which two ESIs act as EPAC2 selective antagonists with negligible activity towards EPAC1. Another ESI, CE3F4, with modest selectivity for EPAC1 over EPAC2, has also been reported. The discovery of EPAC specific antagonists represents
1026-495: 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 . 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 : Epinephrine and glucagon affect
1064-519: The muscles to relax faster. 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,
1102-809: The other hand, decreases the level of phosphorylation of these enzymes, which instead promotes lipogenesis. Recall that gluconeogenesis does not occur in myocytes. 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. PKA
1140-426: 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
1178-484: The regulatory and catalytic halves. As a consequence, the regulatory lobe moves away from catalytic lobe, freeing the active site. In addition, cAMP also prompts conformational changes within the regulatory lobe that lead to the exposure of a lipid binding motif, allowing the proper targeting of EPAC1 to the plasma membrane. Entropically favorable changes in protein dynamics have also been implicated in cAMP mediated EPAC activation. Human and mice EPAC1 mRNA expression
EPAC - Misplaced Pages Continue
1216-405: The same term [REDACTED] This disambiguation page lists articles associated with the title EPAC . If an internal link led you here, you may wish to change the link to point directly to the intended article. Retrieved from " https://en.wikipedia.org/w/index.php?title=EPAC&oldid=1241770108 " Category : Disambiguation pages Hidden categories: Short description
1254-517: The so-called central “switchboard” region. The N terminal regulatory lobe is responsible for cAMP binding while the C-terminal lobe contains the nucleotide exchange factor activity. At the basal cAMP-free state, EPAC is kept in an auto-inhibitory conformation, in which the N-terminal lobe folds on top of the C-terminal lobe, blocking the active site. Binding of cAMP to EPAC induces a hinge motion between
1292-486: 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
1330-508: 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
1368-477: 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. 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., although they are still subject to other layers of regulation, including modulation by
1406-471: The very first time, providing a blueprint for all the other protein kinases in a genome (the kinome). 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,
1444-558: 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. 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 ,
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