RAPGEF4

Last updated
RAPGEF4
Protein RAPGEF4 PDB 1o7f.png
Identifiers
Aliases RAPGEF4 , CAMP-GEFII, CGEF2, EPAC, EPAC 2, EPAC2, Nbla00496, Rap guanine nucleotide exchange factor 4
External IDs OMIM: 606058 MGI: 1917723 HomoloGene: 4451 GeneCards: RAPGEF4
Orthologs
SpeciesHumanMouse
Entrez

11069

56508

Ensembl

ENSG00000091428

ENSMUSG00000049044

UniProt

Q8WZA2

Q9EQZ6

RefSeq (mRNA)

NM_001100397
NM_001282899
NM_001282900
NM_001282901
NM_007023

Contents

NM_001204165
NM_001204166
NM_001204167
NM_019688
NM_001355478

RefSeq (protein)

NP_001191094
NP_001191095
NP_001191096
NP_062662
NP_001342407

Location (UCSC) Chr 2: 172.74 – 173.05 Mb Chr 2: 71.81 – 72.09 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Rap guanine nucleotide exchange factor (GEF) 4 (RAPGEF4), also known as exchange protein directly activated by cAMP 2 (EPAC2) is a protein that in humans is encoded by the RAPGEF4 gene. [5] [6] [7]

Epac2 is a target of cAMP, a major second messenger in various cells. Epac2 is coded by the RAPGEF4 gene, and is expressed mainly in brain, neuroendocrine, and endocrine tissues. [8] Epac2 functions as a guanine nucleotide exchange factor for the Ras-like small GTPase Rap upon cAMP stimulation. [8] [9] Epac2 is involved in a variety of cAMP-mediated cellular functions in endocrine and neuroendocrine cells and neurons. [10] [11]

Gene and transcripts

Human Epac2 is coded by RAPGEF4 located at chromosome 2q31-q32, and three isoforms (Epac2A, Epac2B, and Epac2C) are generated by alternate promoter usage and differential splicing. [8] [12] [13] Epac2A (called Epac2 originally) is a multi-domain protein with 1,011 amino acids, and is expressed mainly in brain and neuroendocrine and endocrine tissues such as pancreatic islets and neuroendocrine cells. [8] Epac2A is composed of two regions, an amino-terminal regulatory region and a carboxy-terminal catalytic region. The regulatory region contains two cyclic nucleotide-binding domains (cNBD-A and cNBD-B) and a DEP (Dishevelled, Egl-10, and Pleckstrin) domain. The catalytic region, which is responsible for the activation of Rap, consists of a CDC25 homology domain (CDC25-HD), a Ras exchange motif (REM) domain, and a Ras association (RA) domain. [14] Epac2B is devoid of the first cNBD-A domain and Epac2C is devoid of a cNBD-A and a DEP domain. Epac2B and Epac2C are expressed specifically in adrenal gland [12] and liver, [13] respectively.

Mechanism of action

The crystal structure reveals that the catalytic region of Epac2 interacts with cNBD-B intramolecularly, and in the absence of cAMP is sterically masked by a regulatory region, which thereby inhibits interaction between the catalytic region and Rap1. [15] The crystal structure of the cAMP analog-bound active form of Epac2 in a complex with Rap1B indicates that the binding of cAMP to the cNBD-B domain induces the dynamic conformational changes that allow the regulatory region to rotate away. This conformational change enables access of Rap1 to the catalytic region and allows activation. [15] [16]

Specific agonists

Several Epac-selective cAMP analogs have been developed to clarify the functional roles of Epacs as well those of the Epac-dependent signaling pathway distinct from the PKA-dependent signaling pathway. [17] The modifications of 8-position in the purine structure and 2’-position in ribose is considered to be crucial to the specificity for Epacs. So far, 8-pCPT-2’-O-Me-cAMP (8-pCPT) and its membrane permeable form 8-pCPT-AM are used for their great specificity toward Epacs. Sulfonylurea drugs (SUs), widely used for the treatment of type 2 diabetes through stimulation of insulin secretion from pancreatic β-cells, have also been shown to specifically activate Epac2. [18]

Function

In pancreatic β-cells, cAMP signaling, which can be activated by various extracellular stimuli including hormonal and neural inputs primarily through Gs-coupled receptors, is of importance for normal regulation of insulin secretion to maintain glucose homeostasis. Activation of cAMP signaling amplifies insulin secretion by Epac2-dependent as well as PKA-dependent pathways. [10] Epac2-Rap1 signaling is critical to promote exocytosis of insulin-containing vesicles from the readily releasable pool. [19] In Epac2-mediated exocytosis of insulin granules, Epac2 interacts with Rim2, [20] [21] which is a scaffold protein localized in both plasma membrane and insulin granules, and determines the docking and priming states of exocytosis. [22] [23] In addition, piccolo, a possible Ca2+ sensor protein, [24] interacts with the Epac2-Rim2 complex to regulate cAMP-induced insulin secretion. [22] It is suggested that phospholipase C-ε (PLC-ε), one of the effector proteins of Rap, regulates intracellular Ca2+ dynamics by altering the activities of ion channels such as ATP-sensitive potassium channel, ryanodine receptor, and IP3 receptor. [11] [25] In neurons, Epac is involved in neurotransmitter release in glutamatergic synapses from calyx of Held and in crayfish neuromuscular junction. [26] [27] [28] Epac also has roles in the development of brain by regulation of neurite growth and neuronal differentiation as well as axon regeneration in mammalian tissue. [29] [30] Furthermore, Epac2 may regulate synaptic plasticity, and thus control higher brain functions such as memory and learning. [31] [32] In heart, Epac1 is expressed predominantly, and is involved in the development of hypertrophic events by chronic cAMP stimulation through β-adrenergic receptors. [33] In contrast, chronic stimulation of Epac2 may be a cause of cardiac arrhythmia through CaMKII-dependent diastolic sarcoplasmic reticulum (SR) Ca2+ release in mice. [34] [35] Epac2 also is involved in GLP-1-stimulated atrial natriuretic peptide (ANP) secretion from heart. [36]

Clinical implications

As Epac2 is involved in many physiological functions in various cells, defects in the Epac2/Rap1 signaling mechanism could contribute to the development of various pathological states. Studies of Epac2 knockout mice indicate that Epac-mediated signaling is required for potentiation of insulin secretion by incretins (gut hormones released from enteroendocrine cells following meal ingestion) such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide, [37] [38] suggesting that Epac2 is a promising target for treatment of diabetes. In fact, incretin-based diabetes therapies are currently used in clinical practice worldwide; development of Epac2-selective agonists might well lead to the discovery of further novel anti-diabetic drugs. An analog of GLP-1 has been shown to exert a blood pressure-lowering effect by stimulation of atrial natriuretic peptide (ANP) secretion through Epac2. [36] In heart, chronic stimulation of β-adrenergic receptor is known to progress to arrhythmia through an Epac2-dependent mechanism. [34] [35] In brain, up-regulation of Epac1 and down-regulation of Epac2 mRNA are observed in patients with Alzheimer's disease, suggesting roles of Epacs in the disease. [39] An Epac2 rare coding variant is found in patients with autism and could be responsible for the dendritic morphological abnormalities. [40] [41] Thus, Epac2 is involved in the pathogenesis and pathophysiology of various diseases, and represents a promising therapeutic target.

Notes

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">Cyclic nucleotide</span> Cyclic nucleic acid

A cyclic nucleotide (cNMP) is a single-phosphate nucleotide with a cyclic bond arrangement between the sugar and phosphate groups. Like other nucleotides, cyclic nucleotides are composed of three functional groups: a sugar, a nitrogenous base, and a single phosphate group. As can be seen in the cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) images, the 'cyclic' portion consists of two bonds between the phosphate group and the 3' and 5' hydroxyl groups of the sugar, very often a ribose.

<span class="mw-page-title-main">Cyclic nucleotide–gated ion channel</span> Family of transport proteins

Cyclic nucleotide–gated ion channels or CNG channels are ion channels that function in response to the binding of cyclic nucleotides. CNG channels are nonselective cation channels that are found in the membranes of various tissue and cell types, and are significant in sensory transduction as well as cellular development. Their function can be the result of a combination of the binding of cyclic nucleotides and either a depolarization or a hyperpolarization event. Initially discovered in the cells that make up the retina of the eye, CNG channels have been found in many different cell types across both the animal and the plant kingdoms. CNG channels have a very complex structure with various subunits and domains that play a critical role in their function. CNG channels are significant in the function of various sensory pathways including vision and olfaction, as well as in other key cellular functions such as hormone release and chemotaxis. CNG channels have also been found to exist in prokaryotes, including many spirochaeta, though their precise role in bacterial physiology remains unknown.

<span class="mw-page-title-main">Nucleotide exchange factor</span>

Nucleotide exchange factors (NEFs) are proteins that stimulate the exchange (replacement) of nucleoside diphosphates for nucleoside triphosphates bound to other proteins.

Growth hormone–releasing hormone (GHRH), also known as somatocrinin or by several other names in its endogenous forms and as somatorelin (INN) in its pharmaceutical form, is a releasing hormone of growth hormone (GH). It is a 44-amino acid peptide hormone produced in the arcuate nucleus of the hypothalamus.

<span class="mw-page-title-main">Glucagon-like peptide-1</span> Gastrointestinal peptide hormone Involved in glucose homeostasis

Glucagon-like peptide-1 (GLP-1) is a 30- or 31-amino-acid-long peptide hormone deriving from the tissue-specific posttranslational processing of the proglucagon peptide. It is produced and secreted by intestinal enteroendocrine L-cells and certain neurons within the nucleus of the solitary tract in the brainstem upon food consumption. The initial product GLP-1 (1–37) is susceptible to amidation and proteolytic cleavage, which gives rise to the two truncated and equipotent biologically active forms, GLP-1 (7–36) amide and GLP-1 (7–37). Active GLP-1 protein secondary structure includes two α-helices from amino acid position 13–20 and 24–35 separated by a linker region.

<span class="mw-page-title-main">Phosphodiesterase 3</span> Class of enzymes

PDE3 is a phosphodiesterase. The PDEs belong to at least eleven related gene families, which are different in their primary structure, substrate affinity, responses to effectors, and regulation mechanism. Most of the PDE families are composed of more than one gene. PDE3 is clinically significant because of its role in regulating heart muscle, vascular smooth muscle and platelet aggregation. PDE3 inhibitors have been developed as pharmaceuticals, but their use is limited by arrhythmic effects and they can increase mortality in some applications.

Phosphodiesterase 1, PDE1, EC 3.1.4.1, systematic name oligonucleotide 5′-nucleotidohydrolase) is a phosphodiesterase enzyme also known as calcium- and calmodulin-dependent phosphodiesterase. It is one of the 11 families of phosphodiesterase (PDE1-PDE11). Phosphodiesterase 1 has three subtypes, PDE1A, PDE1B and PDE1C which divide further into various isoforms. The various isoforms exhibit different affinities for cAMP and cGMP.

<span class="mw-page-title-main">TRPM2</span> Protein-coding gene in the species Homo sapiens

Transient receptor potential cation channel, subfamily M, member 2, also known as TRPM2, is a protein that in humans is encoded by the TRPM2 gene.

<span class="mw-page-title-main">CREB1</span> Mammalian protein found in Homo sapiens

CAMP responsive element binding protein 1, also known as CREB-1, is a protein that in humans is encoded by the CREB1 gene. This protein binds the cAMP response element, a DNA nucleotide sequence present in many viral and cellular promoters. The binding of CREB1 stimulates transcription.

<span class="mw-page-title-main">RAPGEF1</span> Protein-coding gene in the species Homo sapiens

Rap guanine nucleotide exchange factor 1 is a protein that in humans is encoded by the RAPGEF1 gene.

<span class="mw-page-title-main">RAPGEF3</span> Protein-coding gene in humans

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) is a protein that in humans is encoded by the RAPGEF3 gene.

<span class="mw-page-title-main">RAP2A</span> Protein-coding gene in the species Homo sapiens

Ras-related protein Rap-2a is a protein that in humans is encoded by the RAP2A gene. RAP2A is a member of the Ras-related protein family.

<span class="mw-page-title-main">RIMS2</span> Gene of the species Homo sapiens

Regulating synaptic membrane exocytosis protein 2 is a protein that in humans is encoded by the RIMS2 gene.

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

Calcium-dependent secretion activator 1 is a protein that in humans is encoded by the CADPS gene.

<span class="mw-page-title-main">RPH3AL</span> Protein-coding gene in the species Homo sapiens

Rab effector Noc2 is a protein that in humans is encoded by the RPH3AL gene.

<span class="mw-page-title-main">RAPGEF2</span> Protein-coding gene in the species Homo sapiens

Rap guanine nucleotide exchange factor 2 is a protein that in humans is encoded by the RAPGEF2 gene.

<span class="mw-page-title-main">RAPGEF5</span> Protein-coding gene in the species Homo sapiens

Rap guanine nucleotide exchange factor 5 is a protein that in humans is encoded by the RAPGEF5 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.

<span class="mw-page-title-main">RAP1GAP2</span> Protein-coding gene in the species Homo sapiens

RAP1 GTPase activating protein 2 is a protein in humans that is encoded by the RAP1GAP2 gene.

References

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  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000049044 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ "Entrez Gene: RAPGEF4 Rap guanine nucleotide exchange factor (GEF) 4".
  6. ↑ Kawasaki H, Springett GM, Mochizuki N, Toki S, Nakaya M, Matsuda M, Housman DE, Graybiel AM (December 1998). "A family of cAMP-binding proteins that directly activate Rap1". Science. 282 (5397): 2275–9. Bibcode:1998Sci...282.2275K. doi: 10.1126/science.282.5397.2275 . PMID   9856955.
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  40. ↑ Bacchelli E, Blasi F, Biondolillo M, Lamb JA, Bonora E, Barnby G, Parr J, Beyer KS, Klauck SM, Poustka A, Bailey AJ, Monaco AP, Maestrini E (Nov 2003). "Screening of nine candidate genes for autism on chromosome 2q reveals rare nonsynonymous variants in the cAMP-GEFII gene". Molecular Psychiatry. 8 (11): 916–24. doi: 10.1038/sj.mp.4001340 . PMID   14593429.
  41. ↑ Srivastava DP, Woolfrey KM, Jones KA, Anderson CT, Smith KR, Russell TA, Lee H, Yasvoina MV, Wokosin DL, Ozdinler PH, Shepherd GM, Penzes P (2012). "An autism-associated variant of Epac2 reveals a role for Ras/Epac2 signaling in controlling basal dendrite maintenance in mice". PLOS Biology. 10 (6): e1001350. doi: 10.1371/journal.pbio.1001350 . PMC   3383751 . PMID   22745599.
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