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Neuritin is a member of the neurotrophic factor family, which is activated by neural activity and neurotrophins, and promotes neurite growth and branching. It has shown to play an important role in neuronal plasticity and regeneration. It is also involved in other biological processes such as angiogenesis, tumorigenesis and immunomodulation. Thus far, however, the primary mechanisms of neuritin, including whether or not it acts through a receptor or which downstream signals might be activated following binding, are not fully understood. Recent evidence suggests that neuritin may be a potential therapeutic target in several neurodegenerative diseases. This review focuses on the recent advances in studies regarding the newly identified functions of neuritin and the signaling pathways related to these functions. We also discuss current hot topics and difficulties in neuritin research.

Neuritin is an important neurotrophin that regulates neural development, synaptic plasticity, and neuronal survival. Elucidating the downstream molecular signaling is important for potential therapeutic applications of neuritin in neuronal dysfunctions. We previously showed that neuritin up-regulates transient potassium outward current (IA) subunit Kv4.2 expression and increases IA densities, in part by activating the insulin receptor signaling pathway. Molecular mechanisms of neuritin-induced Kv4.2 expression remain elusive. Here, we report that the Ca(2+)/calcineurin (CaN)/nuclear factor of activated T-cells (NFAT) c4 axis is required for neuritin-induced Kv4.2 transcriptional expression and potentiation of IA densities in cerebellum granule neurons. We found that neuritin elevates intracellular Ca(2+) and increases Kv4.2 expression and IA densities; this effect was sensitive to CaN inhibition and was eliminated in Nfatc4(-/-) mice but not in Nfatc2(-/-) mice. Stimulation with neuritin significantly increased nuclear accumulation of NFATc4 in cerebellum granule cells and HeLa cells, which expressed IR. Furthermore, NFATc4 was recruited to the Kv4.2 gene promoter loci detected by luciferase reporter and chromatin immunoprecipitation assays. More importantly, data obtained from cortical neurons following adeno-associated virus-mediated overexpression of neuritin indicated that reduced neuronal excitability and increased formation of dendritic spines were abrogated in the Nfatc4(-/-) mice. Together, these data demonstrate an indispensable role for the CaN/NFATc4 signaling pathway in neuritin-regulated neuronal functions.

Oat contains different components that possess antioxidant properties; no study to date has addressed the antioxidant effect of the extract of oat bran on the cellular level. Therefore, the present study focuses on the investigation of the protective effect of oat bran extract by enzymatic hydrolysates on human dermal fibroblast injury induced by hydrogen peroxide (H(2)O(2)). Kjeldahl determination, phenol-sulfuric acid method, and high-performance liquid chromatography (HPLC) analysis indicated that the enzymatic products of oat bran contain a protein amount of 71.93%, of which 97.43% are peptides with a molecular range from 438.56 to 1301.01 Da. Assays for 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity indicate that oat peptide-rich extract has a direct and concentration-dependent antioxidant activity. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) colorimetric assay and the TdT-mediated digoxigenin-dUTP nick-end labeling (TUNEL) assay for apoptosis showed that administration of H(2)O(2) in human dermal fibroblasts caused cell damage and apoptosis. Pre-incubation of human dermal fibroblasts with the Oatp for 24 h markedly inhibited human dermal fibroblast injury induced by H(2)O(2), but application oat peptides with H(2)O(2) at same time did not. Pre-treatment of human dermal fibroblasts with Oatp significantly reversed the H(2)O(2)-induced decrease of superoxide dismutase (SOD) and the inhibition of malondialdehyde (MDA). The results demonstrate that oat peptides possess antioxidant activity and are effective against H(2)O(2)-induced human dermal fibroblast injury by the enhanced activity of SOD and decrease in MDA level. Our results suggest that oat bran will have the potential to be further explored as an antioxidant functional food in the prevention of aging-related skin injury.

Background: Neuritin is a new neurotrophic factor. The receptors for binding neuritin and its downstream signaling effectors, however, remain unclear. Results: Neuritin increases Kv4.2-mediated IA in rat cerebellar granule neurons by activating the insulin receptor pathway. Conclusion: Neuritin may act as a ligand of the insulin receptor. Significance: Our findings reveal an unanticipated role of the insulin receptor in previously unrecognized neuritin-mediated signaling., Neuritin is a new neurotrophic factor discovered in a screen to identify genes involved in activity-dependent synaptic plasticity. Neuritin also plays multiple roles in the process of neural development and synaptic plasticity. The receptors for binding neuritin and its downstream signaling effectors, however, remain unclear. Here, we report that neuritin specifically increases the densities of transient outward K+ currents (IA) in rat cerebellar granule neurons (CGNs) in a time- and concentration-dependent manner. Neuritin-induced amplification of IA is mediated by increased mRNA and protein expression of Kv4.2, the main α-subunit of IA. Exposure of CGNs to neuritin markedly induces phosphorylation of ERK (pERK), Akt (pAkt), and mammalian target of rapamycin (pmTOR). Neuritin-induced IA and increased expression of Kv4.2 are attenuated by ERK, Akt, or mTOR inhibitors. Unexpectedly, pharmacological blockade of insulin receptor, but not the insulin-like growth factor 1 receptor, abrogates the effect of neuritin on IA amplification and Kv4.2 induction. Indeed, neuritin activates downstream signaling effectors of the insulin receptor in CGNs and HeLa. Our data reveal, for the first time, an unanticipated role of the insulin receptor in previously unrecognized neuritin-mediated signaling.

Citalopram, a selective serotonin (5-HT) reuptake inhibitor (SSRI) as well as an antidepressant, is thought to exert its effects by increasing synaptic 5-HT levels. However, few studies have addressed the possibility that citalopram has other molecular mechanisms of action. We examined the effects of citalopram on delayed rectifier outward K+ current (IK) in mouse cortical neurons. Extracellular citalopram reversibly inhibited IK in a dose-dependent manner and significantly shifted both steady-state activation and inactivation curves toward hyperpolarization. Neither 5-HT itself nor antagonists of 5-HT and dopamine receptors could abolish citalopram-induced inhibition of IK. In addition, intracellular application of GTPγ-S similarly failed to prevent the inhibition of IK by citalopram. When applied intracellularly, citalopram had no effect on IK and did not influence the reduction of IK induced by extracellular citalopram. The effect of citalopram was use dependent, but not frequency dependent, and it did not require channel opening. Electrophysiological recordings in acute cortical slice showed that citalopram significantly reduced the action potential (AP) firing frequency of cortical neurons and increased action potential duration (APD). The selective Kv2.1 subunit blocker Jingzhaotoxin-III (JZTX-III) did not abolish citalopram-induced IK inhibition. Transfection of HEK293 cells with Kv2.1 or Kv2.2 constructs indicated that citalopram mainly inhibited Kv2.2 current. We suggest that citalopram-induced inhibition of IK in mouse cortical neurons is independent of G-protein-coupled receptors and might exert its antidepressant effects by enhancing presynaptic efficiency. Our results may help to explain some of the unknown therapeutic effects of citalopram. © 2011 Wiley Periodicals, Inc.

Animal studies have shown that electromagnetic field exposure may interfere with the activity of brain cells, thereby generating behavioral and cognitive disturbances. However, the underlying mechanisms and possible preventions are still unknown. In this study, we used a mouse model to examine the effects of exposure to extremely low-frequency (50 Hz) electromagnetic fields (ELF MFs) on a recognition memory task and morphological changes of hippocampal neurons. The data showed that ELF MFs exposure (1 mT, 12 h/day) induced a time-dependent deficit in novel object associative recognition memory and also decreased hippocampal dendritic spine density. This effect was observed without corresponding changes in spontaneous locomotor activity and was transient, which has only been seen after exposing mice to ELF MFs for 7-10 days. The over-expression of hippocampal neuritin, an activity-dependent neurotrophic factor, using an adeno-associated virus (AAV) vector significantly increased the neuritin level and dendritic spine density. This increase was paralleled with ELF MFs exposure-induced deficits in recognition memory and reductions of dendritic spine density. Collectively, our study provides evidence for the association between ELF MFs exposure, impairment of recognition memory and resulting changes in hippocampal dendritic spine density. Neuritin prevented this ELF MFs-exposure-induced effect by increasing the hippocampal spine density.

Extremely low-frequency (50Hz) electromagnetic fields (ELF MFs) are ubiquitously present in various environments during daily life. The major sources of ELF MFs pertaining to the general public are in-house installations, household appliances and power lines. Animal studies have shown that ELF MFs exposure may interfere with the activity of brain cells, thereby generating behavioral and cognitive disturbances. However, the underlying mechanisms and possible preventions are still unknown. In our preliminary studies, we found that ICR mice that were exposed to ELF MFs had deficits in hippocampus-dependent recognition memory but no concurrent changes in their locomotor activity. Further experiments revealed that ELF MFs exposure reduced dendritic spine densities of hippocampal CA1 pyramidal cells. Meanwhile, there was no significant effect on dendritic spine diameter or length. Since previous work has shown that neuritin, an important neurotrophin, has the ability to increase the spine density of hippocampal pyramidal neurons, we decided to explore whether neuritin is capable of reversing ELF MFs exposure-induced decreases in dendritic spine density. To this end, adeno-associated virus serotype 9 (AAV9) vectors carrying human neuritin cDNA were produced and stereotaxically injected into the CA1 region of the mouse hippocampus (0.2µl per mouse) 7 days before exposure to ELF MFs. Two control groups were injected in hippocampus with the same volume of AAV-GFP or saline. Western blot analysis indicated that the expression of neuritin was increased by 60.2 ± 5.8% in the hippocampus. We then quantified the effects of AAV9-mediated neuritin over-expression on hippocampal dendritic spine number and subsequent recognition memory in mice of both non-ELF MFs and ELF MFs exposure groups. After a 2.5-week infection period, a significant increase in spine density was observed in the AAV-neuritin group. On the other hand, there was no significant difference in dendritic diameter or length among all three groups of mice. Additionally, after ELF MFs exposure (1mT) for 12 h/day for 10 days, the spine density of pyramidal neurons obtained from neuritin-overexpression mice was no longer reduced. Consequently, the recognition memory test of AAV-neuritin mice showed a significant increase in recognition index when compared to AAV-control mice. Collectively, our study provided evidence for the association between ELF MFs exposure, impairment of recognition memory, and resulting changes in hippocampal dendritic spine density. Furthermore, overexpression of neuritin has the ability to prevent the ELF MFs-exposure-induced effect by increasing the hippocampal spine density.

As molecular profiling data continue to accumulate, the design of integrative computational analyses that can provide insights into the dynamic aspects of cancer progression becomes feasible. Here, we present a novel computational method for the construction of cancer progression models based on the analysis of static tumor samples. We demonstrate the reliability of the method with simulated data, and describe the application to breast cancer data. Our findings support a linear, branching model for breast cancer progression. An interactive model facilitates the identification of key molecular events in the advance of disease to malignancy. Electronic supplementary material The online version of this article (doi:10.1186/s13059-014-0440-0) contains supplementary material, which is available to authorized users.

Neuritin is a new member of the neurotrophic factor family, whose gene is named cpg15 (candidate plasticity-related gene 15) and can be activated by neural activity or neurotrophins (NTs). Experiments show that neuritin is able to promote the growth and branching of neurites, and plays an important role in neuronal plasticity and neuronal regeneration. Recent studies have proved that neuritin is not only involved in the regulation of various physiological functions in the nervous system, but also related in angiogenesis and tumorigenesis. Here we review the mechanisms involved in cpg15 expression and regulation, biological effects of neuritin, and how neuritin plays its biological activities. The hot issues and difficulties in the study of neuritin are also discussed.

Neuregulin-1 (NRG-1) is a member of a family of neurotrophic factors that is required for the differentiation, migration, and development of neurons. NRG-1 signaling is thought to contribute to both neuronal development and the neuropathology of schizophrenia, which is believed to be a neurodevelopmental disorder. However, few studies have investigated the role of NRG-1 on voltage-gated ion channels. In this study, we report that NRG-1 specifically increases the density of transient outward K+ currents ( IA) in rat cerebellar granule neurons (CGNs) in a time-dependent manner without modifying the activation or inactivation properties of IA channels. The increase in IA density is mediated by increased protein expression of Kv4.2, the main α-subunit of the IA channel, most likely by upregulation of translation. The effect of NRG-1 on IA density and Kv4.2 expression was only significant in immature neurons. Mechanistically, both Akt and mammalian target of rapamycin (mTOR) signaling pathways are required for the increased NRG-1-induced IA density and expression of Kv4.2. Moreover, pharmacological blockade of the ErbB4 receptor reduced the effect of NRG-1 on IA density and Kv4.2 induction. Our data reveal, for the first time, that stimulation of ErbB4 signaling by NRG-1 upregulates the expression of K+ channel proteins via activation of the Akt/mTOR signaling pathway and plays an important role in neuronal development and maturation. NRG1 does not acutely change IA and delayed-rectifier outward ( IK) of rat CGNs, suggesting that it may not alter excitability of immature neurons by altering potassium channel property.

In addition to their neurotoxic role in Alzheimer's disease (AD), β-amyloid peptides (Aβs) are also known to play physiological roles. Here, we show that recombinant Aβ40 significantly increased the outward current of the GABAA receptor containing (GABAAα6) in rat cerebellar granule neurons (CGNs). The Aβ40-mediated increase in GABAAα6 current was mediated by an increase in GABAAα6 protein expression at the translational rather than the transcriptional level. The exposure of CGNs to Aβ40 markedly induced the phosphorylation of ERK (pERK) and mammalian target of rapamycin (pmTOR). The increase in GABAAα6 current and expression was attenuated by specific inhibitors of ERK or mTOR, suggesting that the ERK and mTOR signaling pathways are required for the effect of Aβ40 on GABAAα6 current and expression in CGNs. A pharmacological blockade of the p75 neurotrophin receptor (p75NTR), but not the insulin or α7-nAChR receptors, abrogated the effect of Aβ40 on GABAAα6 protein expression and current. Furthermore, the expression of GABAAα6 was lower in CGNs from APP−/− mice than in CGNs from wild-type mice. Moreover, the internal granule layer (IGL) in APP−/− mice was thinner than the IGL in wild-type mice. The injection of Aβ40 into the cerebellum reversed this effect, and the application of p75NTR blocking antibody abolished the effects of Aβ40 on cerebellum morphology in APP−/− mice. Our results suggest that low concentrations of Aβ40 play a role in regulating CGN maturation through p75NTR. In addition to its neurotoxic role in Alzheimer's disease, Aβ is known to play important physiological roles. Whether Aβ improves neuronal development and maturation remains elusive. Our results demonstrate that low concentrations of Aβ40 significantly increase the GABAA receptor α6 subunit expression and associated current in cerebellar granule neurons (CGNs) via the p75NTR and MEK/ERK pathway. Aβ also increases the thickness of the internal granule layer in APP−/− mice cerebellum. Our data provide new evidence for the role of Aβ40 in regulating the maturation of CGNs.

Although the modulation of Ca(2+) channel activity by extremely low-frequency electromagnetic fields (ELF-EMF) has been studied previously, few reports have addressed the effects of such fields on the activity of voltage-activated Na(+) channels (Na(v)). Here, we investigated the effects of ELF-EMF on Na(v) activity in rat cerebellar granule cells (GCs). Our results reveal that exposing cerebellar GCs to ELF-EMF for 10-60 min significantly increased Na(v) currents (I(Na)) by 30-125% in a time- and intensity-dependent manner. The Na(v) channel steady-state activation curve, but not the steady-state inactivation curve, was significantly shifted (by 5.2 mV) towards hyperpolarization by ELF-EMF stimulation. This phenomenon is similar to the effect of intracellular application of arachidonic acid (AA) and prostaglandin E(2) (PGE(2)) on I(Na) in cerebellar GCs. Increases in intracellular AA, PGE(2) and phosphorylated PKA levels in cerebellar GCs were observed following ELF-EMF exposure. Western blottings indicated that the Na(V) 1.2 protein on the cerebellar GCs membrane was increased, the total expression levels of Na(V) 1.2 protein were not affected after exposure to ELF-EMF. Cyclooxygenase inhibitors and PGE(2) receptor (EP) antagonists were able to eliminate this ELF-EMF-induced increase in phosphorylated PKA and I(Na). In addition, ELF-EMF exposure significantly enhanced the activity of PLA(2) in cerebellar GCs but did not affect COX-1 or COX-2 activity. Together, these data demonstrate for the first time that neuronal I(Na) is significantly increased by ELF-EMF exposure via a cPLA2 AA PGE(2) EP receptors PKA signaling pathway.

(+)-SKF 10047 (N-allyl-normetazocine) is a prototypic and specific sigma-1 receptor agonist that has been used extensively to study the function of sigma-1 receptors. (+)-SKF 10047 inhibits K(+), Na(+) and Ca2+ channels via sigma-1 receptor activation. We found that (+)-SKF 10047 inhibited Na(V)1.2 and Na(V)1.4 channels independently of sigma-1 receptor activation. (+)-SKF 10047 equally inhibited Na(V)1.2/1.4 channel currents in HEK293T cells with abundant sigma-1 receptor expression and in COS-7 cells, which barely express sigma-1 receptors. The sigma-1 receptor antagonists BD 1063,BD 1047 and NE-100 did not block the inhibitory effects of (+)-SKF-10047. Blocking of the PKA, PKC and G-protein pathways did not affect (+)-SKF 10047 inhibition of Na(V)1.2 channel currents. The sigma-1 receptor agonists Dextromethorphan (DM) and 1,3-di-o-tolyl-guanidine (DTG) also inhibited Na(V)1.2 currents through a sigma-1 receptor-independent pathway. The (+)-SKF 10047 inhibition of Na(V)1.2 currents was use- and frequency-dependent. Point mutations demonstrated the importance of Phe(1764) and Tyr(1771) in the IV-segment 6 domain of the Na(V)1.2 channel and Phe(1579) in the Na(V)1.4 channel for (+)-SKF 10047 inhibition. In conclusion, our results suggest that sigma-1 receptor agonists directly inhibit Na(V)1.2/1.4 channels and that these interactions should be given special attention for future sigma-1 receptor function studies.

Cyproheptadine (CPH) is a histamine- and serotonin-receptor antagonist, and its effects are observed recently in the modulation of multiple intracellular signals. In this study, we used cortical neurons and HEK-293 cells transfected with Kv2.1 α-subunit to address whether CPH modify neural voltage-gated K(+) channels by a mechanism independent of its serotonergic and histaminergic properties. Our results demonstrate that intracellularly delivered CPH increased the I(K) by reducing the activity of protein kinas A (PKA). Inhibition of G(i) eliminated the CPH-induced effect on both the I(K) and PKA. Blocking of 5-HT-, M-, D(2)-, H(1)- or H(2)-type GPCR receptors with relevant antagonists did not eliminate the CPH-induced effect on the I(K). Antagonists of the sigma-1 receptor, however, blocked the effect of CPH. Moreover, the inhibition of sigma-1 by siRNA knockdown significantly reduced the CPH-induced effect on the I(K). On the contrary, sigma-1 receptor agonist mimicked the effects of CPH on the induction of I(K). A ligand-receptor binding assay indicated that CPH bound to the sigma-1 receptor. Similar effect of CPH were obtained from HEK-293 cells transfected with the α-subunit of Kv2.1. In overall, we reveal for the first time that CPH enhances the I(K) by modulating activity of PKA, and that the associated activation of the sigma-1 receptor/G(i)-protein pathway might be involved. Our findings illustrate an uncharacterized effect of CPH on neuron excitability through the I(K), which is independent of histamine H(1) and serotonin receptors.