Regulating the Ubiquitin/Proteasome Pathway Via cAMP-signaling: Neuroprotective Potential

Huang, He; Wang, Hu; Figueiredo‐Pereira, Maria E.

doi:10.1007/s12013-013-9628-2

Cited by 27 publications

(16 citation statements)

References 126 publications

(179 reference statements)

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“…Adenylyl cyclases (ACs) and phosphodiesterases (PDEs) which synthesize and hydrolyze cAMP, respectively, play a crucial role in modulating intracellular cAMP levels (Houslay and Adams, 2003; Huang et al, 2013). Therefore, we examined the possibility of ACs and PDEs as potential targets for ethanol and synaptamide action using specific inhibitors (Fig.…”

Section: Resultsmentioning

confidence: 99%

N-Docosahexaenoylethanolamine ameliorates ethanol-induced impairment of neural stem cell neurogenic differentiation

Rashid

Kim

2016

Neuropharmacology

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Previous studies demonstrated that prenatal exposure to ethanol interferes with embryonic and fetal development, and causes abnormal neurodevelopment. Docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid highly enriched in the brain, was shown to be essential for proper brain development and function. Recently, we found that N-docosahexenoyethanolamine (synaptamide), an endogenous metabolite of DHA, is a potent PKA-dependent neurogenic factor for neural stem cell (NSC) differentiation. In this study, we demonstrate that ethanol at pharmacologically relevant concentrations down regulates cAMP signaling in NSC and impairs neurogenic differentiation. In contrast, synaptamide reverses ethanol-impaired NSC neurogenic differentiation through counter-acting on the cAMP production system. NSC exposure to ethanol (25-50 mM) for 4 days dose-dependently decreased the number of Tuj-1 positive neurons and PKA/CREB phosphorylation with a concomitant reduction of cellular cAMP. Ethanol-induced cAMP reduction was accompanied by the inhibition of G-protein activation and expression of adenylyl cyclase (AC) 7 and AC8, as well as PDE4 upregulation. In contrast to ethanol, synaptamide increased cAMP production, GTPγS binding, and expression of AC7 and AC8 isoforms in a cAMP-dependent manner, offsetting the ethanol-induced impairment in neurogenic differentiation. These results indicate that synaptamide can reduce ethanol-induced impairment of neuronal differentiation by counter-affecting shared targets in G-protein coupled receptor (GPCR)/cAMP signaling. The synaptamide-mediated mechanism observed in this study may offer a possible avenue for ameliorating the adverse impact of fetal alcohol exposure on neurodevelopment.

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Section: Resultsmentioning

confidence: 99%

N-Docosahexaenoylethanolamine ameliorates ethanol-induced impairment of neural stem cell neurogenic differentiation

Rashid

Kim

2016

Neuropharmacology

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“…Activating cAMP signaling is known to be neuroprotective [78] and to have a positive effect on the UPP [34], which in contrast is inhibited by PGJ2 [41,47,76,90]. Therefore, we explored if increasing intracellular cAMP with PACAP27 would prevent neuronal loss induced by PGJ2.…”

Section: Resultsmentioning

confidence: 99%

“…In regard to the ubiquitinated proteins, PGJ2 impairs the UPP by targeting different components of this pathway including (a) the 26S proteasome by perturbing its assembly [65,90] and oxidatively modifying the S6ATPase (Rpt3) subunit [37], (b) inhibiting deubiquitinating enzymes [41,47,50,61], and (c) causing the accumulation/aggregation of ubiquitinated (Ub) proteins [51]. It is likely that PACAP27 can override the negative effect of PGJ2 on the proteasome because several components of the UPP are up-regulated by activation of the cAMP signaling [34], including proteasome subunits, thus leading to an increase in proteasome activity [62]. However, PACAP27 may be unable to protect UPP components such as UCH-L1 and other de-ubiquitinating enzymes, which are covalently modified at specific cysteine residues by PGJ2 [41,61].…”

Section: Discussionmentioning

confidence: 99%

PACAP27 prevents Parkinson-like neuronal loss and motor deficits but not microglia activation induced by prostaglandin J2

Shivers

Nikolopoulou

Machlovi

et al. 2014

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Neuroinflammation is a major risk factor in Parkinson disease (PD). Alternative approaches are needed to treat inflammation, as anti-inflammatory drugs such as NSAIDs that inhibit cyclooxygenase-2 (COX-2) can produce devastating side effects, including heart attack and stroke. New therapeutic strategies that target factors downstream of COX-2, such as prostaglandin J2 (PGJ2), hold tremendous promise because they will not alter the homeostatic balance offered by COX-2 derived prostanoids. In the current studies, we report that repeated microinfusion of PGJ2 into the substantia nigra of non-transgenic mice, induces three stages of pathology that mimic the slow-onset cellular and behavioral pathology of PD: mild (one injection) when only motor deficits are detectable, intermediate (two injections) when neuronal and motor deficits as well as microglia activation are detectable, and severe (four injections) when dopaminergic neuronal loss is massive accompanied by microglia activation and motor deficits. Microglia activation was evaluated in vivo by positron emission tomography (PET) with [11C](R)PK11195 to provide a regional estimation of brain inflammation. PACAP27 reduced dopaminergic neuronal loss and motor deficits induced by PGJ2, without preventing microglia activation. The latter could be problematic in that persistent microglia activation can exert long-term deleterious effects on neurons and behavior. In conclusion, this PGJ2-induced mouse model that mimics in part chronic inflammation, exhibits slow-onset PD-like pathology and is optimal for testing diagnostic tools such as PET, as well as therapies designed to target the integrated signaling across neurons and microglia, to fully benefit patients with PD.

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“…The two families of cAMP effectors, PKA and Epac, regulate mechanisms for precise and integrated control of cAMP signaling pathways. PKA and Epac may act independently, synergistically or antagonistically in controlling specific cellular functions [16][17][18][34][35][36][37][38]. In this study, we showed that PKA and Epac contribute to cAMP-induced GFAP expression, while PKA, rather than Epac, is responsible for cAMP-dependent morphological changes.…”

Section: Discussionmentioning

confidence: 75%

Protein kinase A and Epac activation by cAMP regulates the expression of glial fibrillary acidic protein in glial cells

Sugimoto

Miwa

Nakamura

et al. 2016

ARCH BIOL SCI BELGRA

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Cyclic adenosine monophosphate (cAMP) controls differentiation in several types of cells during brain development. However, the molecular mechanism of cAMP-controlled differentiation is not fully understood. We investigated the role of protein kinase A (PKA) and exchange protein directly activated by cAMP (Epac) on cAMP-induced glial fibrillary acidic protein (GFAP), an astrocyte marker, in cultured glial cells. B92 glial cells were treated with cAMP-elevating drugs, an activator of adenylate cyclase, phosphodiesterase inhibitor and a ß adrenal receptor agonist. These cAMP-elevating agents induced dramatic morphological changes and expression of GFAP. A cAMP analog, 8-Br-cAMP, which activates Epac as well as PKA, induced GFAP expression and morphological changes, while another cAMP analog, 8-CPT-cAMP, which activates Epac with greater efficacy when compared to PKA, induced GFAP expression but very weak morphological changes. Most importantly, the treatment with a PKA inhibitor partially reduced cAMP-induced GFAP expression. Taken together, these results indicate that cAMP-elevating drugs lead to the induction of GFAP via PKA and/or Epac activation in B92 glial cells.

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Regulating the Ubiquitin/Proteasome Pathway Via cAMP-signaling: Neuroprotective Potential

Cited by 27 publications

References 126 publications

N-Docosahexaenoylethanolamine ameliorates ethanol-induced impairment of neural stem cell neurogenic differentiation

N-Docosahexaenoylethanolamine ameliorates ethanol-induced impairment of neural stem cell neurogenic differentiation

PACAP27 prevents Parkinson-like neuronal loss and motor deficits but not microglia activation induced by prostaglandin J2

Protein kinase A and Epac activation by cAMP regulates the expression of glial fibrillary acidic protein in glial cells

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