BMB Reports 2021; 54(3): 149-156  https://doi.org/10.5483/BMBRep.2021.54.3.233
Epac: new emerging cAMP-binding protein
Kyungmin Lee*
Laboratory for Behavioral Neural Circuitry and Physiology, Department of Anatomy, Brain Science & Engineering Institute, School of Medicine, Kyungpook National University, Daegu 41944, Korea
Correspondence to: Tel: +82-53-420-4803; Fax: +82-53-422-9195; E-mail: irislkm@knu.ac.kr
Received: October 15, 2020; Revised: November 11, 2020; Accepted: November 30, 2020; Published online: February 28, 2021.
© Korean Society for Biochemistry and Molecular Biology. All rights reserved.

cc This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
The well-known second messenger cyclic adenosine monophosphate (cAMP) regulates the morphology and physiology of neurons and thus higher cognitive brain functions. The discovery of exchange protein activated by cAMP (Epac) as a guanine nucleotide exchange factor for Rap GTPases has shed light on protein kinase A (PKA)-independent functions of cAMP signaling in neural tissues. Studies of cAMP-Epac-mediated signaling in neurons under normal and disease conditions also revealed its diverse contributions to neurodevelopment, synaptic remodeling, and neurotransmitter release, as well as learning, memory, and emotion. In this mini-review, the various roles of Epac isoforms, including Epac1 and Epac2, highly expressed in neural tissues are summarized, and controversies or issues are highlighted that need to be resolved to uncover the critical functions of Epac in neural tissues and the potential for a new therapeutic target of mental disorders.
Keywords: Brain, Cognitive function, Epac, Neuron, Synapse
INTRODUCTION

Epac (exchange protein activated by 3’-5’-cyclic adenosine monophosphate [cAMP]) has been investigated functionally and pathophysiologically as a potential therapeutic target of various diseases since it was identified in the late 90s as a novel cAMP target protein by two independent groups (1, 2). Two variants of Epac (Epac1 and Epac2) act as cAMP guanine-nucleotide exchange factors (GEFs) to activate the small GTPases Rap, Rap1, and Rap2 in a protein kinase A (PKA)-independent manner (1, 2), and Epac-activated Rap controls a variety of biological processes (3). The Epac1 and Epac2 proteins are encoded by two different genes: RAPGEF3 (chromosome 12:47,734, 363-47,771,040 for human; chromosome 15:97,744,770-97, 767,972 for mouse) and RAPGEF4 (chromosome 2:172,735, 274-173,052,893 for human; Chromosome 2: 71,981,240-72, 257,474 for mouse), respectively, which both give rise to multiple transcripts. Among potential transcripts produced from Rapgef3, transcript variant 1 of Epac1 encoding the longest isoform, Epac1A with 923 amino acids has been well studied relatively to other transcripts or splicing variants, but differences in functional significance and tissue expression distribution of Epac1 isoforms still remain unclear (4). Contrast to Epac1, transcriptional variants from alternative promoters and splicing variants encoding Epac2 isoforms, Epac2A1, Epac2A2, Epac2B, and Epac2C and tissue distribution of Epac2 protein have been studied well in mice (5) and it is well conserved across human (Table 1). Whereas Epac1 is ubiquitously expressed in nearly every tissue, Epac2 has been detected only in the brain, adrenal glands, pancreas, and liver (5). Interestingly, Epac2 iso-forms Epac2A1, Epac2A2, Epac2B, and Epac2C exhibit distinctive patterns of expression (5). Epac1 and Epac2 proteins, meanwhile, have considerable similarities in structure and they have the amino-terminal regulatory region and carboxyl-terminal catalytic region in common. The regulatory region is composed of a cyclic nucleotide-binding (CNB) domain for functional binding of cAMP and Epac activation, and a Dishevelled, Egl-10, Pleckstrin (DEP) domain. On the other hand, the catalytic region comprises a RAS exchange motif (REM) domain, a RAS-association (RA) domain, and a guanine nucleotide ex-change factor for Ras-like small GTPases (RasGEF) domain, also known as CDC25 homology domain (Fig. 1). The DEP domain is involved in plasma membrane localization of Epac1 and subcellular localization of Epac2. The REM region stabilizes the RasGEF domain without direct interaction with the small GTPases. The RA domain helps perinuclear localization of Epac1 and regulate plasma membrane localization of Epac2 (4, 6). Structurally, Epac1 consists of identical structural subdomains with those found in Epac2B although their exon sequences and transcripts are different (Fig. 1).

In the brain, Epac2 expression in neurons is more abundant than but works with Epac1 to regulate neural function (2). To elucidate the roles of Epac1 and Epac2 in the central nervous system, specific inhibitors and activators have been utilized, such as ESI-05, a selective inhibitor of Epac2 (7), Sp-8-BnT-cAMPS (S0220), a selective Epac2 activator (8), and 8-pCPT-2’-O-Me-cAMP (8-CPT [D-007]), which is an activator of Epac1 and Epac2 (8). Although 8-CPT is commonly used in vitro and in vivo as a general activator of Epac, it was revealed that it is a much more effective activator of Epac1 than Epac2 (5). Thus, the effects of 8-CPT may reflect the role of Epac1 or Epac2 according to the expression level of each isoform in cells or tissues. Additionally, knockout (KO) mouse models have been used to assess the functions of these proteins, such as mice deficient in Epac1 (9, 10), Epac2A (11), or all isoforms of Epac2 (12).

The use of a variety of research tools has revealed the involvement of Epac in a diversity of neuronal functions, including neurotransmitter release (13), neurite growth, and neuronal/glial differentiation (14, 15), and in higher cognitive functions, such as memory, learning, and social interaction (12). This mini-review summarizes recent findings from research on Epac1 and Epac2, and provides an overview of their diverse roles in the central nervous system. Findings in this emerging field may have implications both for the clinics and for society, and may provide new insights into novel therapeutic approaches for neurological and psychiatric disorders.

ROLES OF EPAC AT SYNAPSES AND IN NEURONS

Synaptic remodeling and plasticity

It is well known that synaptic remodeling of spine structures (16) and synaptic plasticity (17) are the two key synaptic mechanisms that underlie the anatomical and physiological bases, respectively, of learning and memory formation. Among the variety of molecular events that mediate these processes, cAMP represents a key intracellular signal that regulates the morphological plasticity of dendritic spines (18) and long-term potentiation (LTP) of synapses (19-21) through cAMP response element binding protein (CREB) or PKA. However, Epac is also involved in synaptic morphology and plasticity.

In cultured mature rat cortical neurons, which express smaller amounts of Epac1 than Epac2, 8-CPT-induced activation of Epac2 results in spine shrinkage, decreased spine motility, and depressed excitatory transmission, with removal of GluA2/3-containing AMPA receptors from synapses. These Epac2-mediated effects were confirmed in vivo in cortical neurons of Epac2 KO mice (12, 22). Conversely, point mutations of Epac2 associated with autism (23) induce spine enlargement and stabilization (15). Moreover, studies on the effect of Epac2 on synaptic proteins have revealed that Epac2 balances neuronal excitation and inhibition by stabilizing excitatory synapses and increasing inhibitory synapses (22).

Further electrophysiological studies using Epac2 KO mice or ESI-05 have shown that Epac2 is involved in cAMP-dependent potentiation of hippocampal mossy fiber synapses (13) and LTP at parallel fiber-to-Purkinje cell synapses via activation of GluA3-containing AMPA receptors (24). Yang et al. demonstrated that KO mice deficient in Epac1 and Epac2 had impaired hippocampal LTP at CA3-CA1 Schaffer collateral synapses but not long-term depression (LTD) as a result of reduced presynaptic glutamate release, whereas no synaptic deficits were detected in the hippocampi of Epac2 KO mice (10). However, deletion of Epac2A results in a failure of NMDA receptor-dependent LTD at the Schaffer collateral-CA1 synapses of hippocampus (11).

Although specific effect of Epac1 or Epac2 was not demonstrated in the following studies, electrophysiological studies using 8-CPT revealed that the Epac-dependent increase of glutamate release at hippocampal excitatory synapses (25) is mediated by phospholipase C (26). Moreover, Epac activation contributes to the maintenance of LTP (27) and pituitary adenylate cyclase-activating polypeptide (PACAP)-induced LTD (28) via extracel-lular signal-regulated protein kinase (ERK) and p38 mitogen-activated protein kinase (MAPK), respectively, in the hippocampus (Fig. 2A). Therefore, effects of Epac on synaptic remodeling and plasticity may be different according to isoforms and these issues remain unresolved yet.

Neurodevelopment

Neurite and axonal growth: Epac1 and Epac2 are differentially regulated during nervous tissue development. Whereas Epac1 is abundantly expressed in the brain at embryonic and neonatal periods but is almost undetectable in adulthood, Epac2 is lowly expressed at embryonic and neonatal stages and increased in the adult brain (29). These findings suggest that Epac1 has a more influential role than Epac2 in neurite outgrowth during development. In support of this, knockdown of Epac1 expression with short hairpin RNA (shRNA) in cultured hippocampal neurons results in fewer polarized neurons with shorter axons via Rap1B inhibition, and cultured hippocampal neurons from Epac1 KO mice display delayed polarization (9). In pheochromocytoma (PC-12) cells, Epac1 is involved in panaxydol-induced axonal growth via the Rap1-ERK-CREB pathway (30). However, through a Rap-independent mechanism, cAMP-mediated Epac1-dependent Rit activation induced by PACAP38 results in CREB-dependent neurite outgrowth in PC-6 cells (a subline of PC-12 cells) (31). Interestingly, cAMP- and Rap1-independent functions of Epac1 have a reverse effect on neurite outgrowth. For example, in the Neuro2a neuroblastoma cell line, Epac1 accumulates at the plasma membrane because of the lack of importin β1 and neither binds to cAMP nor activates Rap1, thereby inhibiting neurite outgrowth (Fig. 2B) (32).

We cannot rule out the possible involvement of Epac2 in neurite and axonal outgrowth, as both Epac1 and Epac2 are expressed throughout the brain. Indeed, RNA interference-mediated knockdown of Epac2 disrupts the architecture of basal dendrites via inhibition of Ras signaling in mature cortical neurons (33). Furthermore, activation of Epac2 with the specific agonist S-220 enhances the outgrowth of neurites from postnatal rat cortical neurons in vitro (34). Additionally, short-interfering RNA (siRNA)-mediated knockdown of Epac1 and Epac2 reduces neurite outgrowth, blocks cAMP-induced neurite growth (29), and eliminates the chemoattraction of rat dorsal root ganglia neuron growth cones to netrin-1 (35). Compatibly with these results, Epac1 and Epac2 activation by 8-CPT is involved in rolipram-induced neurite outgrowth from rat dorsal root ganglia neurons (36) and the conversion of PKA-specific cAMP from a proliferative to an antiproliferative signal in PC-12 cells by promoting neurite outgrowth (37). Nevertheless, 8-CPT-mediated activation of Epac does not affect neurite outgrowth in spiral ganglion neurons (Fig. 1A) (38). Further studies, including in vivo analyses, are needed to identify the precise roles of Epac proteins in neurite and axonal outgrowth.

Neurogenesis and glial differentiation: Although little is known about the role of Epac in neural differentiation during embryonic neurogenesis, Epac2 may be involved in adult neurogenesis in the ventricular-subventricular zone (V-SVZ) and subgranular zone (SGZ) of dentate gyrus, where it is expressed in GFAP-positive neural stem cells and doublecortin-positive neuroblasts and progenitor cells (39). A study using adult Epac2 KO mice showed that this protein is required for progenitor cell proliferation and neurogenesis in the SGZ (40). Other studies reported a role of Epac in the differentiation of glial cells, including astrocytes and oligodendrocytes. PACAP-induced astrocytic differentiation of neural precursor cells is mediated by Epac2A activation via calcium ion influx, leading to increased intracellular concentrations (14). Moreover, inhibition of Epac2 with ESI-05 revealed that Epac2 promotes cAMP-dependent differentiation of cultured rat oligodendrocyte precursor cells by regulating the expression of myelin basic protein (41). In addition, whereas cAMP-dependent proliferation of Schwann cells requires PKA activity, activation of Epac by 8-CPT is antiproliferative and also impacts the cAMP-dependent differentiation and myelin formation in peripheral Schwann cells (42). Thus, although little is known about an exact role of Epac1 in neurogenesis and glial differentiation, Epac, especially Epac2 isoform, appears critical for normal development of neurons and astrocytes, and might provide a new therapeutic target to enhance remyelination in the central and peripheral nervous systems.

Cell death

Cell death is critical for homeostasis in organisms by eliminating excess and injured cells. Apoptosis and autophagy have been characterized as major types of programmed cell death (43). Although the roles of Epac have been extensively studied in cancer (44), less is known about the role of Epac on cell death in the central nervous system.

Apoptosis: Whereas cAMP-PKA signaling is neuroprotective, activation of Epac, such as by 8-CPT or adeno-associated virus-mediated overexpression of Epac1 or Epac2, induces apoptosis of cultured mouse cortical neurons by p38 MAPK-induced upregulation of Bim (known as a Bcl-2 interacting member and Bcl-2-like protein 11) (Fig. 2A) (45). Moreover, cortical neurons of Epac1 KO mice are protected from 3-propionic acid-induced apoptosis, and neurons cultured from Epac1 KO mice show decreased expression of Bim mRNA and protein (45). Furthermore, by using ESI-05 and a rat model of traumatic brain injury, inhibition of Epac2 was found to reduce the associated neuronal apoptosis (46, 47). Although these findings suggest that Epac1 and Epac2 have a proapoptotic effect in neurons, Epac exhibits antiapoptotic effects in other cells, such as hematopoietic B-CLL cells (48), macrophages (49), and cardiomyocytes (50). Thus, the pro- or antiapoptotic roles of Epac may vary according to cell type and may reflect the differential localization of Epac protein via membrane targeting activities of dishevelled, Egl-10, the pleckstrin domain (51), and Ras association domain (52).

mTOR-independent autophagy: Autophagy is an intracellular lysosomal process for the degradation of endogenous or exogenous materials in the cytoplasm (53). Two signaling pathways are involved in this process: mammalian target of rapamycin (mTOR)-dependent and mTOR-independent pathways (54). Contrary to the role of PKA in mTOR-independent autophagy (55), cAMP-Epac signaling may inhibit this autophagy by activating a series of components of Rap2B-PLC-ε-IP3 and Ca2+calpain-Gsα pathways (Fig. 2A) (56). In PC-12 cells, 8-CPT delays the clearance of autophagy substrates, and autophagy is induced by inhibiting Epac-activated Rap2B, indicating that Rap2B acts as a downstream regulator of Epac in the mTOR-independent autophagy pathway (56).

ROLES OF EPAC IN COGNITION AND MENTAL DISORDERS

Learning and memory

Several in vivo studies using KO mice demonstrated that the Epac isoforms impact spatial learning and memory. Mice with double KO of both Epac1 and Epac2 show spatial learning and memory impairments and deficits in reversal learning in the Morris water maze (MWM); however, single KO mice deficient in either Epac 1 or Epac2 exhibit normal spatial learning (10). However, another group revealed that despite normal performance in the MWM, Epac2 KO mice had a deficit in contextual fear conditioning, with reduced freezing behavior (40). Additionally, inhibition of Epac2 by injection of siRNA resulted in impaired fear memory retrieval in mice (57). Epac2A KO mice similarly show normal spatial learning and memory in MWM and IntelliCage tests but impaired reversal learning, suggesting that Epac2A plays a role in behavioral flexibility (11). Unlike Epac2 KO (40), Epac2A KO mice are insensitive to painful stimuli (11), and so it is not known if this isoform contributes to contextual fear conditioning, but they exhibit normal reward-based reinforcement learning (58).

Stress and affective disorders

In a postmortem study comparing protein levels of Epac1 and Epac2 in brain tissues from control and suicide groups, Epac2 was significantly higher in the prefrontal cortices and hippocampus of suicide victims with major depression disorder, whereas Epac1 protein expression did not differ from that in the controls (59). Contrary to data from human study, in the hippocampi of mice exposed to acute restraint stress which is used to model depression and anxiety disorders (60), the expression of Epac1 and Epac2 mRNAs was higher in female wild-type mice, and Epac KO mice showed delayed nuclear localization of glucocorticoid receptors along with altered serum corticosterone levels (60). In a study conducted by Zhou and colleagues, Epac2 KO mice displayed anxious and depressive behaviors in normal environments: they spent less time in the center of an open field and exhibited increased immobility during forced swimming test (40). However, other studies found no evidence that Epac2 deletion alters anxiety (10, 12). Although further study is needed to clarify these discrepancies, the current evidence suggests that Epac1 and Epac2 differentially affect emotional behaviors by regulating cellular responses to stress.

Autism spectrum disorders

Screens for genes on human chromosome 2q revealed nonsynonymous variants in RAPGEF4 (encoding Epac2) in individuals with autistic phenotypes (23). Furthermore, Epac2 KO mice exhibit social interaction impairments in three-chamber tests and ultrasonic vocalization studies, although they show normal working memory and repetitive behaviors (12). Epac2A KO mice also display a stereotypic behavior: making the same decision consecutively during a dynamic foraging task for reward-based reinforcement learning, demonstrating an abnormal decision-making process and perseverative behaviors such as those observed in individuals with autism spectrum disorders (58). These studies also suggest that there are abnormalities of cortical structures, including disrupted cortical columnar organization in the anterior cingulate cortex (12) and a lower density of parvalbumin-expressing GABAergic interneurons in the ventrolateral orbitofrontal cortex (58). However, the role of Epac2 in autistic behavioral phenotypes is still debated. Whereas double deficiency for Epac genes impairs social interactions in mice, this impairment is not seen in single Epac1 or Epac2 KOs (10). Thus, further detailed studies are needed to evaluate the role of Epac in autism.

CONCLUSION

Since the Epac protein was identified in 1998, accumulating data from scientific studies have clarified PKA-independent cAMP functions via Epac in various cell types and tissues. Moreover, specific activators/inhibitors of Epac isoforms and genetic manipulations have helped uncover the specific roles of Epac1 and Epac2 in a variety of tissues. This mini-review summarizes the specific roles of Epac1 and Epac2 in neural cells and tissues (Fig. 2B and 2C). Despite growing evidence suggesting that Epac is an essential protein in the cAMP signaling pathway in neural tissues, a lot of issues remain unsolved. For instance, Epac isoform-specific or Epac localization-dependent anatomical and physiological functions in neurons and higher cognitive functions during different life stages, from embryo to old age, similarly remain shrouded in mystery. Further isoform-specific gene manipulations or drug development specific for Epac2 isoforms will be helpful to elucidate their specific functions. In addition, the roles of Epac1 and/or Epac2 in molecular, physiological, and behavioral phenotypes determined in KO mice need further study. This is also critical for discovering the precise role of Epac proteins in the molecular and pathophysiological mechanisms underlying various diseases, including neurodegenerative and mental disorders.

ACKNOWLEDGEMENTS

K.L. was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education [NRF-2019R1F1A1063932].

CONFLICTS OF INTEREST

The author has no conflicting interests.

Figures
Fig. 1. Schematic representation of domain structure and genomic organization of Epac protein isoforms. Epac1 and Epac2 consist of the N-terminal regulatory region and the C-terminal catalytic region in common, which are composed of functional multi-domains. The regulatory region contains a cyclic nucleotide-binding (CNB) domain and a dishevelled, Egl-10, Pleckstrin (DEP) domain. The CNB domain of Epac1 and CNB-B domain of Epac2 bind cAMP with a high affinity leading to Epac protein activation. The extra CNB-A domain of Epac2A1 and Epac2A2 bind cAMP with a relatively low affinity compared with the conserved CNB-B domain and is not involved in activation of Epac2. The Dishevelled, Egl-10, Pleckstrin (DEP) domain has a role in the subcellular localization of Epac protein. In the catalytic region, a RAS exchange motif (REM) domain interacting with the guanine nucleotide exchange factor (GEF) region stabilizes a GEF for Ras-like small GTPases (RasGEF) domain which is responsible for biological function of Epac protein. The RAS-association (RA) domain regulates perinuclear localization of Epac1 and plasma membrane localization of Epac2.
Fig. 2. Roles of Epac in synaptic plasticity, neurodevelopment, and cell death. (A) Effects of 8-CPT-induced activation and gene deletion of Epac. The 8-CPT activates both Epac1 and Epac2 in neural tissues. Note the stronger effect of 8-CPT on Epac1 activation (thick arrow) than Epac2 (thin arrow). Activation of Epac protein including Epac1 and Epac2 isoforms contributes to LTP maintenance via extracellular signal-regulated kinase 1/2 (ERK) activation, PACAP-mediated LTD induction via activation of p38 mitogen-activated protein kinases (MAPK), apoptosis by p38 MAPK-induced upregulation of Bim (Bcl-2-interacting mediator known as a Bcl-2 like protein 11), and inhibition of mTOR-independent autophagy activation through Rap2B/PLCε/inositol 1,4,5-trisphosphate (IP3) signaling pathway. However, effects of 8-CPT-induced Epac activation on neurite outgrowth and synaptic glutamate release are quite different and are not determined yet in neural tissue. (B) Role of Epac1 in neurite and axonal growth. Epac1 is involved in axonal growth through Rap1/ERK/cAMP-response element binding protein (CREB) signaling pathway. In Rap-independent manner, Epac1 plays a role in enhancement or inhibition of neurite growth via Rit/CREB activation or accumulation itself near plasma membrane regardless of binding to cAMP, respectively. (C) Role Epac2 and Epac2A isoform in neural tissues. Epac2 involves in adult neurogenesis and glial differentiation, apoptotic cell death and induces synaptic spine shrinkage and neurite outgrowth. The asymmetric expression of Ras/Epac2/Rap in dendritic compartments of cortical neurons affects the distribution of phosphorylated BRaf (p-BRaf) in dendrites and then maintenance of basal dendrite complexity in cortical neurons. However, the effect of Epac2 on LTP induction and maintenance is a controversial issue showing different results according to neural tissues. Epac2A isoform is required for LTD induction but not LTP in the hippocampus and astrocyte differentiation during development. LTP, long-term potentiation; LTD, long-term depression.
Table

Summary of Epac2 isoforms

Protein name Epac2A1 Epac2A2 Epac2B Epac2C
Transcript name
NCBI Transcript variant 1 Transcript variant 2 Transcript variant 3
Ensembl RAPGEF4-202 RAPGEF4-203 RAPGEF4-201
ID
NCBI
Transcript NM_001204165.1 NM_019688.2 NM_001204166.1
Protein NP_001191094.1 NP_062662.1 NP_001191095.1
EBI
Transcript ENSMUST00000090826.11 ENSMUST00000102698.9 ENSMUST00000028525.5
Protein ENSMUSP00000088336.5 ENSMUSP00000099759.3 ENSMUSP00000028525.5
Exon number 31 30 28
Protein length (a.a) 1011 993 867 696
Protein expression in tissuea
Brain + +
Adrenal gl. + +
Pancreas + +
Kidney +
Liver +
Orthologous splicing isoform in human (NCBI ID) Transcript variant 1 (NM_007023.4) Transcript variant 8 (NM_001375866.1) Transcript variant 2 (NM_001100397.2)

aCitation from reference (5).


References
  1. de Rooij J, Rehmann H, van Triest M, Cool RH, Wittinghofer A and Bos JL (2000) Mechanism of regulation of the Epac family of cAMP-dependent RapGEFs. J Biol Chem 275, 20829-20836
    Pubmed CrossRef
  2. Kawasaki H, Springett GM, Mochizuki N et al (1998) A family of cAMP-binding proteins that directly activate Rap1. Science 282, 2275-2279
    Pubmed CrossRef
  3. Frische EW and Zwartkruis FJ (2010) Rap1, a mercenary among the Ras-like GTPases. Dev Biol 340, 1-9
    Pubmed CrossRef
  4. Banerjee U and Cheng X (2015) Exchange protein directly activated by cAMP encoded by the mammalian rapgef3 gene: structure, function and therapeutics. Gene 570, 157-167
    Pubmed KoreaMed CrossRef
  5. Hoivik EA, Witsoe SL, Bergheim IR et al (2013) DNA methylation of alternative promoters directs tissue specific expression of Epac2 isoforms. PLoS One 8, e67925
    Pubmed KoreaMed CrossRef
  6. Lezoualc'h F, Fazal L, Laudette M and Conte C (2016) Cyclic AMP sensor EPAC proteins and their role in cardio-vascular function and disease. Circ Res 118, 881-897
    Pubmed CrossRef
  7. Rehmann H (2013) Epac-inhibitors: facts and artefacts. Sci Rep 3, 3032
    Pubmed KoreaMed CrossRef
  8. Schwede F, Bertinetti D, Langerijs CN et al (2015) Structure-guided design of selective Epac1 and Epac2 agonists. PLoS Biol 13, e1002038
    Pubmed KoreaMed CrossRef
  9. Munoz-Llancao P, Henriquez DR, Wilson C et al (2015) Exchange protein directly activated by cAMP (EPAC) regulates neuronal polarization through Rap1B. J Neurosci 35, 11315-11329
    Pubmed KoreaMed CrossRef
  10. Yang Y, Shu X, Liu D et al (2012) EPAC null mutation impairs learning and social interactions via aberrant regulation of miR-124 and Zif268 translation. Neuron 73, 774-788
    Pubmed KoreaMed CrossRef
  11. Lee K, Kobayashi Y, Seo H et al (2015) Involvement of cAMP-guanine nucleotide exchange factor II in hippocampal long-term depression and behavioral flexibility. Mol Brain 8, 38
    Pubmed KoreaMed CrossRef
  12. ivastava DP Sr, Jones KA, Woolfrey KM et al (2012) Social, communication, and cortical structural impairments in Epac2-deficient mice. J Neurosci 32, 11864-11878
    Pubmed KoreaMed CrossRef
  13. Fernandes HB, Riordan S, Nomura T et al (2015) Epac2 mediates cAMP-dependent potentiation of neurotransmission in the hippocampus. J Neurosci 35, 6544-6553
    Pubmed KoreaMed CrossRef
  14. Seo H and Lee K (2016) Epac2 contributes to PACAP-induced astrocytic differentiation through calcium ion influx in neural precursor cells. BMB Rep 49, 128-133
    Pubmed KoreaMed CrossRef
  15. Woolfrey KM, ivastava DP Sr, Photowala H et al (2009) Epac2 induces synapse remodeling and depression and its disease-associated forms alter spines. Nat Neurosci 12, 1275-1284
    Pubmed KoreaMed CrossRef
  16. Matus A (1999) Postsynaptic actin and neuronal plasticity. Curr Opin Neurobiol 9, 561-565
    Pubmed CrossRef
  17. Martin SJ, Grimwood PD and Morris RG (2000) Synaptic plasticity and memory: an evaluation of the hypothesis. Annu Rev Neurosci 23, 649-711
    Pubmed CrossRef
  18. Murphy DD and Segal M (1997) Morphological plasticity of dendritic spines in central neurons is mediated by activation of cAMP response element binding protein. Proc Natl Acad Sci U S A 94, 1482-1487
    Pubmed KoreaMed CrossRef
  19. Deisseroth K, Bito H and Tsien RW (1996) Signaling from synapse to nucleus: postsynaptic CREB phosphorylation during multiple forms of hippocampal synaptic plasticity. Neuron 16, 89-101
    Pubmed CrossRef
  20. Impey S, Mark M, Villacres EC, Poser S, Chavkin C and Storm DR (1996) Induction of CRE-mediated gene expression by stimuli that generate long-lasting LTP in area CA1 of the hippocampus. Neuron 16, 973-982
    Pubmed CrossRef
  21. Nguyen PV and Kandel ER (1996) A macromolecular synthesis-dependent late phase of long-term potentiation requiring cAMP in the medial perforant pathway of rat hippocampal slices. J Neurosci 16, 3189-3198
    Pubmed KoreaMed CrossRef
  22. Jones KA, Sumiya M, Woolfrey KM, ivastava DP Sr and Penzes P (2019) Loss of EPAC2 alters dendritic spine morphology and inhibitory synapse density. Mol Cell Neurosci 98, 19-31
    Pubmed KoreaMed CrossRef
  23. Bacchelli E, Blasi F, Biondolillo M et al (2003) Screening of nine candidate genes for autism on chromosome 2q reveals rare nonsynonymous variants in the cAMP-GEFII gene. Mol Psychiatry 8, 916-924
    Pubmed CrossRef
  24. Gutierrez-Castellanos N, Da Silva-Matos CM, Zhou K et al (2017) Motor learning requires purkinje cell synaptic potentiation through activation of AMPA-receptor subunit GluA3. Neuron 93, 409-424
    Pubmed KoreaMed CrossRef
  25. Gekel I and Neher E (2008) Application of an Epac activator enhances neurotransmitter release at excitatory central synapses. J Neurosci 28, 7991-8002
    Pubmed KoreaMed CrossRef
  26. Ferrero JJ, Alvarez AM, Ramirez-Franco J et al (2013) beta-Adrenergic receptors activate exchange protein directly activated by cAMP (Epac), translocate Munc13-1, and enhance the Rab3A-RIM1alpha interaction to potentiate glutamate release at cerebrocortical nerve terminals. J Biol Chem 288, 31370-31385
    Pubmed KoreaMed CrossRef
  27. Gelinas JN, Banko JL, Peters MM, Klann E, Weeber EJ and Nguyen PV (2008) Activation of exchange protein activated by cyclic-AMP enhances long-lasting synaptic potentiation in the hippocampus. Learn Mem 15, 403-411
    Pubmed KoreaMed CrossRef
  28. Ster J, de Bock F, Bertaso F et al (2009) Epac mediates PACAP-dependent long-term depression in the hippocampus. J Physiol 587, 101-113
    Pubmed KoreaMed CrossRef
  29. Murray AJ and Shewan DA (2008) Epac mediates cyclic AMP-dependent axon growth, guidance and regeneration. Mol Cell Neurosci 38, 578-588
    Pubmed CrossRef
  30. Li WP, Ma K, Jiang XY et al (2018) Molecular mechanism of panaxydol on promoting axonal growth in PC12 cells. Neural Regen Res 13, 1927-1936
    Pubmed KoreaMed CrossRef
  31. Shi GX, Rehmann H and Andres DA (2006) A novel cyclic AMP-dependent Epac-Rit signaling pathway contributes to PACAP38-mediated neuronal differentiation. Mol Cell Biol 26, 9136-9147
    Pubmed KoreaMed CrossRef
  32. Baameur F, Singhmar P, Zhou Y et al (2016) Epac1 interacts with importin beta1 and controls neurite outgrowth independently of cAMP and Rap1. Sci Rep 6, 36370
    Pubmed KoreaMed CrossRef
  33. ivastava DP Sr, Woolfrey KM, Jones KA et al (2012) An autism-associated variant of Epac2 reveals a role for Ras/Epac2 signaling in controlling basal dendrite maintenance in mice. PLoS Biol 10, e1001350
    Pubmed KoreaMed CrossRef
  34. Guijarro-Belmar A, Viskontas M, Wei Y, Bo X, Shewan D and Huang W (2019) Epac2 elevation reverses inhibition by chondroitin sulfate proteoglycans in vitro and transforms postlesion inhibitory environment to promote axonal outgrowth in an ex vivo model of spinal cord injury. J Neurosci 39, 8330-8346
    Pubmed KoreaMed CrossRef
  35. Murray AJ, Tucker SJ and Shewan DA (2009) cAMP-dependent axon guidance is distinctly regulated by Epac and protein kinase A. J Neurosci 29, 15434-15444
    Pubmed KoreaMed CrossRef
  36. Boomkamp SD, McGrath MA, Houslay MD and Barnett SC (2014) Epac and the high affinity rolipram binding conformer of PDE4 modulate neurite outgrowth and myelination using an in vitro spinal cord injury model. Br J Pharmacol 171, 2385-2398
    Pubmed KoreaMed CrossRef
  37. Kiermayer S, Biondi RM, Imig J et al (2005) Epac activation converts cAMP from a proliferative into a differentiation signal in PC12 cells. Mol Biol Cell 16, 5639-5648
    Pubmed KoreaMed CrossRef
  38. Xu N, Engbers J, Khaja S, Xu L, Clark JJ and Hansen MR (2012) Influence of cAMP and protein kinase A on neurite length from spiral ganglion neurons. Hear Res 283, 33-44
    Pubmed KoreaMed CrossRef
  39. Seo H and Lee K (2019) Cell-specific expression of Epac2 in the subventricular and subgranular zones. Mol Brain 12, 113
    Pubmed KoreaMed CrossRef
  40. Zhou L, Ma SL, Yeung PK et al (2016) Anxiety and depression with neurogenesis defects in exchange protein directly activated by cAMP 2-deficient mice are ameliorated by a selective serotonin reuptake inhibitor, Prozac. Transl Psychiatry 6, e881
    Pubmed KoreaMed CrossRef
  41. Simon K, Hennen S, Merten N et al (2016) The orphan G protein-coupled receptor GPR17 negatively regulates oli-godendrocyte differentiation via Galphai/o and Its downstream effector molecules. J Biol Chem 291, 705-718
    Pubmed KoreaMed CrossRef
  42. Bacallao K and Monje PV (2013) Opposing roles of PKA and EPAC in the cAMP-dependent regulation of schwann cell proliferation and differentiation [corrected]. PLoS One 8, e82354
    Pubmed KoreaMed CrossRef
  43. Nikoletopoulou V, Markaki M, Palikaras K and Tavernarakis N (2013) Crosstalk between apoptosis, necrosis and autophagy. Biochim Biophys Acta 1833, 3448-3459
    Pubmed CrossRef
  44. Almahariq M, Mei FC and Cheng X (2016) The pleiotropic role of exchange protein directly activated by cAMP 1 (EPAC1) in cancer: implications for therapeutic intervention. Acta Biochim Biophys Sin (Shanghai) 48, 75-81
    Pubmed KoreaMed CrossRef
  45. Suzuki S, Yokoyama U, Abe T et al (2010) Differential roles of Epac in regulating cell death in neuronal and myocardial cells. J Biol Chem 285, 24248-24259
    Pubmed KoreaMed CrossRef
  46. Zhang L, Zhang L, Liu H et al (2018) Inhibition of Epac2 attenuates neural cell apoptosis and improves neurological deficits in a rat model of traumatic brain injury. Front Neurosci 12, 263
    Pubmed KoreaMed CrossRef
  47. Zhuang Y, Xu H, Richard SA et al (2019) Inhibition of EPAC2 attenuates intracerebral hemorrhage-induced secondary brain injury via the p38/BIM/Caspase-3 pathway. J Mol Neurosci 67, 353-363
    Pubmed CrossRef
  48. Tiwari S, Felekkis K, Moon EY, Flies A, Sherr DH and Lerner A (2004) Among circulating hematopoietic cells, B-CLL uniquely expresses functional EPAC1, but EPAC1-mediated Rap1 activation does not account for PDE4 in-hibitor-induced apoptosis. Blood 103, 2661-2667
    Pubmed CrossRef
  49. Misra UK and Pizzo SV (2005) Coordinate regulation of forskolin-induced cellular proliferation in macrophages by protein kinase A/cAMP-response element-binding protein (CREB) and Epac1-Rap1 signaling: effects of silencing CREB gene expression on Akt activation. J Biol Chem 280, 38276-38289
    Pubmed CrossRef
  50. Kwak HJ, Park KM, Choi HE, Chung KS, Lim HJ and Park HY (2008) PDE4 inhibitor, roflumilast protects cardiomyocytes against NO-induced apoptosis via activation of PKA and Epac dual pathways. Cell Signal 20, 803-814
    Pubmed CrossRef
  51. Dodge-Kafka KL, Soughayer J, Pare GC et al (2005) The protein kinase A anchoring protein mAKAP coordinates two integrated cAMP effector pathways. Nature 437, 574-578
    Pubmed KoreaMed CrossRef
  52. Li Y, Asuri S, Rebhun JF, Castro AF, Paranavitana NC and Quilliam LA (2006) The RAP1 guanine nucleotide exchange factor Epac2 couples cyclic AMP and Ras signals at the plasma membrane. J Biol Chem 281, 2506-2514
    Pubmed CrossRef
  53. Galluzzi L, Baehrecke EH, Ballabio A et al (2017) Molecular definitions of autophagy and related processes. EMBO J 36, 1811-1836
    Pubmed KoreaMed CrossRef
  54. Sarkar S (2013) Regulation of autophagy by mTOR-dependent and mTOR-independent pathways: autophagy dysfunction in neurodegenerative diseases and therapeutic application of autophagy enhancers. Biochem Soc Trans 41, 1103-1130
    Pubmed CrossRef
  55. Ugland H, Naderi S, Brech A, Collas P and Blomhoff HK (2011) cAMP induces autophagy via a novel pathway involving ERK, cyclin E and Beclin 1. Autophagy 7, 1199-1211
    Pubmed CrossRef
  56. Sarkar S, Ravikumar B, Floto RA and Rubinsztein DC (2009) Rapamycin and mTOR-independent autophagy inducers ameliorate toxicity of polyglutamine-expanded huntingtin and related proteinopathies. Cell Death Differ 16, 46-56
    Pubmed CrossRef
  57. Ostroveanu A, van der Zee EA, Eisel UL, Schmidt M and Nijholt IM (2010) Exchange protein activated by cyclic AMP 2 (Epac2) plays a specific and time-limited role in memory retrieval. Hippocampus 20, 1018-1026
    Pubmed CrossRef
  58. Roh M, Lee H, Seo H et al (2020) Perseverative stereotypic behavior of Epac2 KO mice in a reward-based decision making task. Neurosci Res 161, 8-17
    Pubmed CrossRef
  59. Dwivedi Y, Mondal AC, Rizavi HS et al (2006) Differential and brain region-specific regulation of Rap-1 and Epac in depressed suicide victims. Arch Gen Psychiatry 63, 639-648
    Pubmed CrossRef
  60. Aesoy R, Muwonge H, Asrud KS et al (2018) Deletion of exchange proteins directly activated by cAMP (Epac) causes defects in hippocampal signaling in female mice. PLoS One 13, e0200935
    Pubmed KoreaMed CrossRef


This Article


Cited By Articles
  • CrossRef (0)

Author ORCID Information

Funding Information
  • Ministry of Education, Republic of Korea
     
      NRF-2019R1F1A1063932

Collections

Services
Social Network Service

e-submission

Archives