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RAPGEF4

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Protein-coding gene in the species Homo sapiens
RAPGEF4
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; OMA:RAPGEF4 - orthologs
Gene location (Human)
Chromosome 2 (human)
Chr.Chromosome 2 (human)
Chromosome 2 (human)Genomic location for RAPGEF4Genomic location for RAPGEF4
Band2q31.1Start172,735,274 bp
End173,052,893 bp
Gene location (Mouse)
Chromosome 2 (mouse)
Chr.Chromosome 2 (mouse)
Chromosome 2 (mouse)Genomic location for RAPGEF4Genomic location for RAPGEF4
Band2|2 C3Start71,811,584 bp
End72,087,818 bp
RNA expression pattern
Bgee
HumanMouse (ortholog)
Top expressed in
  • right frontal lobe

  • Amygdala

  • dorsolateral prefrontal cortex

  • prefrontal cortex

  • Brodmann area 9

  • cingulate gyrus

  • hippocampus proper

  • anterior cingulate cortex

  • nucleus accumbens

  • right adrenal gland
Top expressed in
  • globus pallidus

  • lateral geniculate nucleus

  • superior frontal gyrus

  • dentate gyrus of hippocampal formation granule cell

  • habenula

  • prefrontal cortex

  • nucleus accumbens

  • anterior amygdaloid area

  • ventral tegmental area

  • lobe of cerebellum
More reference expression data
BioGPS
More reference expression data
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
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_001093867
NP_001269828
NP_001269829
NP_001269830
NP_008954

NP_001362793
NP_001362794
NP_001362795
NP_001362796
NP_001362797
NP_001362798
NP_001362799
NP_001362800
NP_001362801
NP_001362802
NP_001362803
NP_001362804
NP_001362805

NP_001191094
NP_001191095
NP_001191096
NP_062662
NP_001342407

Location (UCSC)Chr 2: 172.74 – 173.05 MbChr 2: 71.81 – 72.09 Mb
PubMed search
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.

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. Epac2 functions as a guanine nucleotide exchange factor for the Ras-like small GTPase Rap upon cAMP stimulation. Epac2 is involved in a variety of cAMP-mediated cellular functions in endocrine and neuroendocrine cells and neurons.

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. 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. 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. 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 and liver, 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. 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.

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. 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.

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. Epac2-Rap1 signaling is critical to promote exocytosis of insulin-containing vesicles from the readily releasable pool. In Epac2-mediated exocytosis of insulin granules, Epac2 interacts with Rim2, which is a scaffold protein localized in both plasma membrane and insulin granules, and determines the docking and priming states of exocytosis. In addition, piccolo, a possible Ca sensor protein, interacts with the Epac2-Rim2 complex to regulate cAMP-induced insulin secretion. It is suggested that phospholipase C-ε (PLC-ε), one of the effector proteins of Rap, regulates intracellular Ca dynamics by altering the activities of ion channels such as ATP-sensitive potassium channel, ryanodine receptor, and IP3 receptor. In neurons, Epac is involved in neurotransmitter release in glutamatergic synapses from calyx of Held and in crayfish neuromuscular junction. 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. Furthermore, Epac2 may regulate synaptic plasticity, and thus control higher brain functions such as memory and learning. In heart, Epac1 is expressed predominantly, and is involved in the development of hypertrophic events by chronic cAMP stimulation through β-adrenergic receptors. In contrast, chronic stimulation of Epac2 may be a cause of cardiac arrhythmia through CaMKII-dependent diastolic sarcoplasmic reticulum (SR) Ca release in mice. Epac2 also is involved in GLP-1-stimulated atrial natriuretic peptide (ANP) secretion from heart.

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, 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. In heart, chronic stimulation of β-adrenergic receptor is known to progress to arrhythmia through an Epac2-dependent mechanism. 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. An Epac2 rare coding variant is found in patients with autism and could be responsible for the dendritic morphological abnormalities. Thus, Epac2 is involved in the pathogenesis and pathophysiology of various diseases, and represents a promising therapeutic target.

Notes

JournalThe 2015 version of this article was updated by an external expert under a dual publication model. The corresponding academic peer reviewed article was published in Gene and can be cited as:
Kenji Sugawara; Tadao Shibasaki; Harumi Takahashi; Susumu Seino (18 September 2015). "Structure and functional roles of Epac2 (Rapgef4)". Gene. Gene Wiki Review Series. 575 (2 Pt 3): 577–583. doi:10.1016/J.GENE.2015.09.029. ISSN 0378-1119. PMC 6636354. PMID 26390815. Wikidata Q38590433.

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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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