RAPGEF4 explained

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.[1] [2] [3]

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.[4] Epac2 functions as a guanine nucleotide exchange factor for the Ras-like small GTPase Rap upon cAMP stimulation.[4] [5] Epac2 is involved in a variety of cAMP-mediated cellular functions in endocrine and neuroendocrine cells and neurons.[6] [7]

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.[4] [8] [9] 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.[4] 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.[10] 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.[11] 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.[12]

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.[13] 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.[14]

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.[6] Epac2-Rap1 signaling is critical to promote exocytosis of insulin-containing vesicles from the readily releasable pool.[15] In Epac2-mediated exocytosis of insulin granules, Epac2 interacts with Rim2,[16] [17] which is a scaffold protein localized in both plasma membrane and insulin granules, and determines the docking and priming states of exocytosis.[18] [19] In addition, piccolo, a possible Ca2+ sensor protein,[20] 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 Ca2+ dynamics by altering the activities of ion channels such as ATP-sensitive potassium channel, ryanodine receptor, and IP3 receptor.[21] In neurons, Epac is involved in neurotransmitter release in glutamatergic synapses from calyx of Held and in crayfish neuromuscular junction.[22] [23] [24] 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.[25] [26] Furthermore, Epac2 may regulate synaptic plasticity, and thus control higher brain functions such as memory and learning.[27] [28] In heart, Epac1 is expressed predominantly, and is involved in the development of hypertrophic events by chronic cAMP stimulation through β-adrenergic receptors.[29] In contrast, chronic stimulation of Epac2 may be a cause of cardiac arrhythmia through CaMKII-dependent diastolic sarcoplasmic reticulum (SR) Ca2+ release in mice.[30] [31] Epac2 also is involved in GLP-1-stimulated atrial natriuretic peptide (ANP) secretion from heart.[32]

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,[33] [34] 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.[35] An Epac2 rare coding variant is found in patients with autism and could be responsible for the dendritic morphological abnormalities.[36] [37] Thus, Epac2 is involved in the pathogenesis and pathophysiology of various diseases, and represents a promising therapeutic target.

Notes and References

  1. Web site: Entrez Gene: RAPGEF4 Rap guanine nucleotide exchange factor (GEF) 4.
  2. Kawasaki H, Springett GM, Mochizuki N, Toki S, Nakaya M, Matsuda M, Housman DE, Graybiel AM . A family of cAMP-binding proteins that directly activate Rap1 . Science . 282 . 5397 . 2275–9 . December 1998 . 9856955 . 10.1126/science.282.5397.2275 . 1998Sci...282.2275K . free .
  3. de Rooij J, Rehmann H, van Triest M, Cool RH, Wittinghofer A, Bos JL . Mechanism of regulation of the Epac family of cAMP-dependent RapGEFs . J. Biol. Chem. . 275 . 27 . 20829–36 . July 2000 . 10777494 . 10.1074/jbc.M001113200 . free .
  4. Kawasaki H, Springett GM, Mochizuki N, Toki S, Nakaya M, Matsuda M, Housman DE, Graybiel AM . A family of cAMP-binding proteins that directly activate Rap1 . Science . 282 . 5397 . 2275–9 . Dec 1998 . 9856955 . 10.1126/science.282.5397.2275. 1998Sci...282.2275K . free .
  5. de Rooij J, Zwartkruis FJ, Verheijen MH, Cool RH, Nijman SM, Wittinghofer A, Bos JL . Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP . Nature . 396 . 6710 . 474–7 . Dec 1998 . 9853756 . 10.1038/24884 . 1998Natur.396..474D . 204996248 .
  6. Seino S, Shibasaki T . PKA-dependent and PKA-independent pathways for cAMP-regulated exocytosis . Physiological Reviews . 85 . 4 . 1303–42 . Oct 2005 . 16183914 . 10.1152/physrev.00001.2005 . 14539206 .
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