The results raise the possibility that depressive symptoms in older persons may be associated with risk of developing AD.

Neurite outgrowth is key to the formation of functional circuits during neuronal development. Neurotrophins, including nerve growth factor (NGF), increase neurite outgrowth in part by altering the function and expression of Ca 2؉ -permeable cation channels. Here we report that transient receptor potential vanilloid 2 (TRPV2) is an intracellular Ca 2؉ -permeable TRPV channel upregulated by NGF via the mitogen-activated protein kinase (MAPK) signaling pathway to augment neurite outgrowth. TRPV2 colocalized with Rab7, a late endosome protein, in addition to TrkA and activated extracellular signal-regulated kinase (ERK) in neurites, indicating that the channel is closely associated with signaling endosomes. In line with these results, we showed that TRPV2 acts as an ERK substrate and identified the motifs necessary for phosphorylation of TRPV2 by ERK. Furthermore, neurite length, TRPV2 expression, and TRPV2-mediated Ca 2؉ signals were reduced by mutagenesis of these key ERK phosphorylation sites. Based on these findings, we identified a previously uncharacterized mechanism by which ERK controls TRPV2-mediated Ca 2؉ signals in developing neurons and further establish TRPV2 as a critical intracellular ion channel in neuronal function.E stablishment of precise neural connections during nervous system development is essential in forming functional circuits. Neurite outgrowth allows for connection and communication between developing neurons and their targets. In the developing peripheral nervous system, nerve growth factor (NGF) is a targetderived extracellular cue necessary for outgrowth (1). Upon binding to its extracellular receptor, NGF activates the phosphoinositide 3-kinase (PI3K) signaling pathway, which is essential for the survival of developing neurons, and the mitogen-activated protein kinase (MAPK) pathway, which promotes differentiation and neurite outgrowth (2, 3). These signaling pathways have numerous downstream effectors in developing neurons, including several Ca 2ϩ -permeable transient receptor potential (TRP) channels (4-8).Thermosensitive TRP channels from the vanilloid subfamily (thermoTRPV channels) consist of four nonselective Ca 2ϩ -permeable cation channels, TRP vanilloid 1 (TRPV1) to TRPV4, originally described as pain and temperature sensors in adult sensory neurons (9-12). Recent evidence suggests, however, that only TRPV1 functions as a molecular sensor of heat and painful stimuli in vivo, while the function of TRPV2 to -4 remains unclear (13-16). TRPV2 and TRPV4 have also been detected in developing peripheral neurons, suggesting that they may play a role in growth programs during development (17, 18). Consistent with this notion, TRPV2 has been implicated in axon outgrowth (18), and critical mutations in TRPV4 result in peripheral axonal neuropathies (19,20). Despite these initial findings, the details by which thermoTRPV channels influence neuronal development remain unknown.Here we explore the molecular mechanisms by which thermoTRPV channels contribute to neurotrophin-mediated peripher...

Selenium (Se) is a micronutrient essential to human health, the function of which is mediated in part by incorporation into a class of proteins known as selenoproteins (SePs). As many SePs serve antioxidant functions, Se has long been postulated to protect against inflammation and cancer development in the gut by attenuating oxidative stress. Indeed, numerous studies over the years have correlated Se levels with incidence and severity of intestinal diseases such as inflammatory bowel disease (IBD) and colorectal cancer (CRC). Similar results have been obtained with the Se transport protein, selenoprotein P (SELENOP), which is decreased in the plasma of both IBD and CRC patients. While animal models further suggest that decreases in Se or SELENOP augment colitis and intestinal tumorigenesis, large-scale clinical trials have yet to show a protective effect in patient populations. In this review, we discuss the function of Se and SELENOP in intestinal diseases and how research into these mechanisms may impact patient treatment.

A broad range of redox-regulated proteins undergo reversible disulfide bond formation on oxidation-prone cysteine residues. Heightened reactivity of the thiol groups in these cysteines also increases susceptibility to modification by organic electrophiles, a property that can be exploited in the study of redox networks. Here, we explored whether divinyl sulfone (DVSF), a thiol-reactive bifunctional electrophile, cross-links oxidant-sensitive proteins to their putative redox partners in cells. To test this idea, previously identified oxidant targets involved in oxidant defense (namely, peroxiredoxins, methionine sulfoxide reductases, sulfiredoxin, and glutathione peroxidases), metabolism, and proteostasis were monitored for cross-link formation following treatment of Saccharomyces cerevisiae with DVSF. Several proteins screened, including multiple oxidant defense proteins, underwent intermolecular and/or intramolecular cross-linking in response to DVSF. Specific redox-active cysteines within a subset of DVSF targets were found to influence cross-linking; in addition, DVSF-mediated cross-linking of its targets was impaired in cells first exposed to oxidants. Since cross-linking appeared to involve redox-active cysteines in these proteins, we examined whether potential redox partners became cross-linked to them upon DVSF treatment. Specifically, we found that several substrates of thioredoxins were cross-linked to the cytosolic thioredoxin Trx2 in cells treated with DVSF. However, other DVSF targets, like the peroxiredoxin Ahp1, principally formed intra-protein cross-links upon DVSF treatment. Moreover, additional protein targets, including several known to undergo S-glutathionylation, were conjugated via DVSF to glutathione. Our results indicate that DVSF is of potential use as a chemical tool for irreversibly trapping and discovering thiol-based redox partnerships within cells.

BASIC AND TRANSLATIONAL ATcapabilities. Thus, colonic SELENOP is the most informative means to assess selenium levels and activity in IBD patients and may serve as a novel biomarker for UC disease severity and identify patients most predisposed to CAC development.