Current Issue : January - March Volume : 2015 Issue Number : 1 Articles : 5 Articles
Serotonin receptors are G-protein-coupled receptors (GPCRs) involved in a variety of psychiatric disorders. G-proteins,\nheterotrimeric complexes that couple to multiple receptors, are activated when their receptor is bound by the\nappropriate ligand. Activation triggers a cascade of further signalling events that ultimately result in cell function\nchanges. Each of the several known G-protein types can activate multiple pathways. Interestingly, since several\nG-proteins can couple to the same serotonin receptor type, receptor activation can result in induction of different\npathways. To reach a better understanding of the role, interactions and expression of G-proteins a literature search\nwas performed in order to list all the known heterotrimeric combinations and serotonin receptor complexes. Public\ndatabases were analysed to collect transcript and protein expression data relating to G-proteins in neural tissues.\nOnly a very small number of heterotrimeric combinations and G-protein-receptor complexes out of the possible\nthousands suggested by expression data analysis have been examined experimentally. In addition this has mostly\nbeen obtained using insect, hamster, rat and, to a lesser extent, human cell lines. Besides highlighting which interactions\nhave not been explored, our findings suggest additional possible interactions that should be examined based on our\nexpression data analysis....
Endoplasmic reticulum (ER) is motile within dendritic spines, but the mechanisms underlying its regulation are\npoorly understood. To address this issue, we have simultaneously imaged morphology and ER content of dendritic\nspines in cultured dissociated mouse hippocampal neurons. Over a 10 min period, spines were highly dynamic,\nwith spines both increasing and decreasing in volume. ER was present in approximately 50% of spines and was also\nhighly dynamic, with a net increase over this period of time. Inhibition of the endogenous activation of NMDA\nreceptors resulted in a reduction in ER growth. Conversely, augmentation of the synaptic activation of NMDA\nreceptors, by elimination of striatal-enriched protein tyrosine phosphatase (STEP), resulted in enhanced ER growth.\nTherefore, NMDA receptors rapidly regulate spine ER dynamics....
Background: Alzheimer�s disease (AD) is characterized by cerebral deposition of ?-amyloid peptide (A?). A? is\nproduced by sequential cleavage of the Amyloid Precursor Protein (APP) by ?- and ?-secretases. Many studies have\ndemonstrated that the internalization of APP from the cell surface can regulate A? production, although the exact\norganelle in which A? is produced remains contentious. A number of recent studies suggest that intracellular\ntrafficking also plays a role in regulating A? production, but these pathways are relatively under-studied. The\ngoal of this study was to elucidate the intracellular trafficking of APP, and to examine the site of intracellular\nAPP processing.\nResults: We have tagged APP on its C-terminal cytoplasmic tail with photoactivatable Green Fluorescent Protein\n(paGFP). By photoactivating APP-paGFP in the Golgi, using the Golgi marker Galactosyltranferase fused to Cyan\nFluorescent Protein (GalT-CFP) as a target, we are able to follow a population of nascent APP molecules from the\nGolgi to downstream compartments identified with compartment markers tagged with red fluorescent protein\n(mRFP or mCherry); including rab5 (early endosomes) rab9 (late endosomes) and LAMP1 (lysosomes). Because\n?-cleavage of APP releases the cytoplasmic tail of APP including the photoactivated GFP, resulting in loss of\nfluorescence, we are able to visualize the cleavage of APP in these compartments. Using APP-paGFP, we show that\nAPP is rapidly trafficked from the Golgi apparatus to the lysosome; where it is rapidly cleared. Chloroquine and the\nhighly selective ?-secretase inhibitor, L685, 458, cause the accumulation of APP in lysosomes implying that APP is\nbeing cleaved by secretases in the lysosome. The Swedish mutation dramatically increases the rate of lysosomal\nAPP processing, which is also inhibited by chloroquine and L685, 458. By knocking down adaptor protein 3\n(AP-3; a heterotetrameric protein complex required for trafficking many proteins to the lysosome) using siRNA, we\nare able to reduce this lysosomal transport. Blocking lysosomal transport of APP reduces A? production by more\nthan a third.\nConclusion: These data suggests that AP-3 mediates rapid delivery of APP to lysosomes, and that the lysosome is a\nlikely site of A? production....
Background: Recent studies have indicated that Toll-like receptor 4 (TLR4), a pathogen-recognition receptor that\ntriggers inflammatory signals in innate immune cells, is also expressed on sensory neurons, implicating its putative\nrole in sensory signal transmission. However, the possible function of sensory neuron TLR4 has not yet been\nformally addressed. In this regard, we investigated the role of TLR4 in itch signal transmission.\nResults: TLR4 was expressed on a subpopulation of dorsal root ganglia (DRG) sensory neurons that express TRPV1.\nIn TLR4-knockout mice, histamine-induced itch responses were compromised while TLR4 activation by LPS did not\ndirectly elicit an itch response. Histamine-induced intracellular calcium signals and inward currents were comparably\nreduced in TLR4-deficient sensory neurons. Reduced histamine sensitivity in the TLR4-deficient neurons was\naccompanied by a decrease in TRPV1 activity. Heterologous expression experiments in HEK293T cells indicated\nthat TLR4 expression enhanced capsaicin-induced intracellular calcium signals and inward currents.\nConclusions: Our data show that TLR4 on sensory neurons enhances histamine-induced itch signal transduction\nby potentiating TRPV1 activity. The results suggest that TLR4 could be a novel target for the treatment of enhanced\nitch sensation....
Parkinson�s disease (PD) is one of the major neurodegenerative disorders. Mitochondrial malfunction is implicated in\nPD pathogenesis. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN)-induced putative kinase 1\n(PINK1), a serine/threonine kinase, plays an important role in the quality control of mitochondria and more than 70\nPINK1 mutations have been identified to cause early-onset PD. However, the regulation of PINK1 gene expression\nremains elusive. In the present study, we identified the transcription start site (TSS) of the human PINK1 gene using\nswitching mechanism at 5�end of RNA transcription (SMART RACE) assay. The TSS is located at 91 bp upstream of\nthe translation start site ATG. The region with 104 bp was identified as the minimal promoter region by deletion\nanalysis followed by dual luciferase assay. Four functional cis-acting nuclear factor kappa-light-chain-enhancer of\nactivated B cells (NFkB)-binding sites within the PINK1 promoter were identified. NFkB overexpression led to the\nup-regulation of PINK1 expression in both HEK293 cells and SH-SY5Y cells. Consistently, lipopolysaccharide (LPS), a\nstrong activator of NFkB, significantly increased PINK1 expression in SH-SY5Y cells. Taken together, our results clearly\nsuggested that PINK1 expression is tightly regulated at its transcription level and NFkB is a positive regulator for\nPINK1 expression....
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