Exchange Protein Directly Activated by cAMP (EPAC) Regulates Neuronal Polarization through Rap1B

Muñoz-Llancao, Pablo; Henríquez, Daniel R.; Wilson, Carlos Pizarro; Bodaleo, Felipe; Boddeke, Erik; Lezoualc’h, Frank; Schmidt, Martina; González-Billault, Christian

doi:10.1523/jneurosci.3645-14.2015

Cited by 27 publications

(26 citation statements)

References 68 publications

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“…The upstream mechanism of Rap1 activation by BDNF has not been fully elucidated. However, it is known that BDNF increases the levels of cAMP increasing the activity of EPAC, a guanine‐exchanging factor involved in Rap1b activation and neuronal polarity [Cheng et al, ; Munoz‐Llancao et al, ].…”

Section: Membrane Dynamics and The Regulation Of Bdnf Signaling And Nmentioning

confidence: 99%

Cellular and molecular mechanisms regulating neuronal growth by brain‐derived neurotrophic factor

et al. 2016

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Brain-derived neurotrophic factor (BDNF) and its receptors TrkB and p75 regulate dendritic and axonal growth during development and maintenance of the mature nervous system; however, the cellular and molecular mechanisms underlying this process are not fully understood. In recent years, several advances have shed new light on the processes behind the regulation of BDNF-mediated structural plasticity including control of neuronal transcription, local translation of proteins, and regulation of cytoskeleton and membrane dynamics. In this review, we summarize recent advances in the field of BDNF signaling in neurons to induce neuronal growth. V C 2016 Wiley Periodicals, Inc.Key Words: BDNF; dendritic growth; signaling; cytoskeleton dynamics; membrane trafficking Introduction T he functionality of the nervous system (NS) depends on the extent of connectivity achieved by neurons. Although there is wide range of neuronal morphologies, neurons are specialized to form part of a given neuronal circuit and thus their morphology must adjust to this task [Gao, 2007]. In this regard, neurons are highly polarized cells composed of two main domains: the somato-dendritic compartment where neurons receive and integrate information from several axonal inputs and axons that are responsible for transmitting the action potential and conveying the information to the next relay in the network. A close relationship between the appropriate development of dendrites and axons and the functionality of the NS has been described. For example, alterations in dendrites, axonal inputs and dendritic spines are linked to neurodevelopmental and neuropathological conditions. Thus, the study of the mechanisms implicated in the regulation of neuronal morphology during development and maintenance of the adult NS is a focus of intense research [Armstrong et al., 1998;Wood et al., 2004;Bronfman et al., 2007;Dickstein et al., 2010;Cabeza et al., 2012;Eiland and McEwen, 2012;Kulkarni and Firestein, 2012].Neuronal morphology is regulated by both intrinsic and extrinsic factors, whose actions are overlapping. The intrinsic factors are described as the action of the genetic program of neurons that leads to a basic pattern of branching. In addition to this, there is an extensive list of molecules grouped as extrinsic factors that shape axonal and dendritic morphology throughout development and in response to sensory experience. These include bone morphogenetic family proteins (BMPs), semaphorins, Reelin, neurotrophins, and neuronal activity, among others [Jan and Jan, 2010]. The mechanisms underlying the effects of external cues to induce dendritic and axonal branching have only begun to be understood, and several steps including stimulation of intracellular signaling pathways to activate specific transcription factors, local synthesis of proteins and cellular membrane addition and turnover are involved. An interesting point of convergence is the effect of these external signals on the stability and dynamics of the cytoskeleton and the activity of molecular mo...

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Section: Membrane Dynamics and The Regulation Of Bdnf Signaling And Nmentioning

confidence: 99%

Cellular and molecular mechanisms regulating neuronal growth by brain‐derived neurotrophic factor

et al. 2016

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“…Epac1 regulates growth of neurites and axons in hippocampal and dorsal root ganglion neurons17242526. In addition, there is evidence that impβ1 is transcribed in axons of damaged dorsal root ganglion neurons and contributes to their recovery46.…”

Section: Resultsmentioning

confidence: 99%

“…For example, it was shown recently that Epac1 depletion reduced polarization of hippocampal neurons in vitro and produced shorter axons. The role of Epac1 in neuronal polarization was ascribed to activation of Rap1b downstream of activation of Epac1 by cAMP, and Rap1b activation is necessary for establishment of polarity in hippocampal neurons26. Thus, the role of Epac1 in promoting axon-formation is thought to occur downstream of cAMP binding to Epac1 leading to Rap1 activation.…”

Section: Discussionmentioning

confidence: 99%

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Epac1 interacts with importin β1 and controls neurite outgrowth independently of cAMP and Rap1

Singhmar¹,

Zhou

Hancock

et al. 2016

Sci Rep

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Exchange protein directly activated by cAMP-1 (Epac1) is a cAMP sensor that regulates multiple cellular functions including cellular migration, proliferation and differentiation. Classically, Epac1 is thought to exert its effects through binding of cAMP leading to a conformational change in Epac1 and its accumulation at the plasma membrane (PM) where it activates Rap1. In search for regulators of Epac1 activity, we show here that importin β1 (impβ1) is an Epac1 binding partner that prevents PM accumulation of Epac1. We demonstrate that in the absence of impβ1, endogenous as well as overexpressed Epac1 accumulate at the PM. Moreover, agonist-induced PM translocation of Epac1 leads to dissociation of Epac1 from impβ1. Localization of Epac1 at the PM in the absence of impβ1, requires residue R82 in its DEP domain. Notably, the PM accumulation of Epac1 in the absence of impβ1 does not require binding of cAMP to Epac1 and does not result in Rap1 activation. Functionally, PM accumulation of Epac1, an Epac1 mutant deficient in cAMP binding, or an Epac1 mutant tethered to the PM, is sufficient to inhibit neurite outgrowth. In conclusion, we uncover a cAMP-independent function of Epac1 at the PM and demonstrate that impβ1 controls subcellular localization of Epac1.

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“…Chotani and his co-researchers proved that serum can induce cAMP-Rap pathway conducted alpha(2)-adrenoceptors expression in vascular smooth muscle cells [42,43]. Epac signaling also contributes to axon specification, elongation and neuronal polarity [44]. These result indicated the significance of Epac-Rap signalling in cardiovascular and neuronal system.…”

Section: Figmentioning

confidence: 92%

Rap-Interacting Proteins are Key Players in the Rap Symphony Orchestra

Guo¹,

An²,

Yang³

et al. 2016

Cell Physiol Biochem

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Rap, a member of the Ras-like small G-protein family, is a key node among G-protein coupled receptors (GPCR), receptor tyrosine kinases (RTKs), ion channels and many other downstream pathways. Rap plays a unique role in cell morphogenesis, adhesion, migration, exocytosis, proliferation, apoptosis and carcinogenesis. The complexity and diversity of Rap functions are tightly regulated by Rap-interacting proteins such as GEFs, GAPs, Rap effectors and scaffold proteins. These interacting proteins decide the subcellular localization of Rap, the interaction modes with downstream Rap effectors and tune Rap as an atypical molecular conductor, coupling extra- and intracellular signals to various pathways. In this review, we summarize four groups of Rap-interacting proteins, highlight their distinctions in Rap-binding properties and interactive modes and discuss their contribution to the spatiotemporal regulation of Rap as well as the implications of targeting Rap-interacting proteins in human cancer therapy.

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Exchange Protein Directly Activated by cAMP (EPAC) Regulates Neuronal Polarization through Rap1B

Cited by 27 publications

References 68 publications

Cellular and molecular mechanisms regulating neuronal growth by brain‐derived neurotrophic factor

Cellular and molecular mechanisms regulating neuronal growth by brain‐derived neurotrophic factor

Epac1 interacts with importin β1 and controls neurite outgrowth independently of cAMP and Rap1

Rap-Interacting Proteins are Key Players in the Rap Symphony Orchestra

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