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RAPGEF4

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RAPGEF4
Protein RAPGEF4 PDB 1o7f.png
Identifiers
AliasesRAPGEF4, CAMP-GEFII, CGEF2, EPAC, EPAC 2, EPAC2, Nbla00496, Rap guanine nucleotide exchange factor 4
External IDsOMIM: 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

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 MbChr 2: 71.98 – 72.26 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/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, , 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[]

References[]

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  26. ^ Gekel I, Neher E (Aug 2008). "Application of an Epac activator enhances neurotransmitter release at excitatory central synapses". The Journal of Neuroscience. 28 (32): 7991–8002. doi:10.1523/JNEUROSCI.0268-08.2008. PMC 6670779. PMID 18685024.
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External links[]

  • Overview of all the structural information available in the PDB for UniProt: Q9EQZ6 (Mouse Rap guanine nucleotide exchange factor 4) at the PDBe-KB.
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