Magnocellular neurones in the supraoptic nucleus and paraventricular nucleus express mRNA for nitric oxide synthase (NOS) and the expression becomes more prominent when the release of vasopressin or oxytocin is stimulated. It has also been reported that NO donors inhibit the electrical activity of supraoptic nucleus neurones, but the mechanism involved in the inhibition remains unclear. In the present study, to know whether modulation of synaptic inputs into supraoptic neurones is involved in the inhibitory effect of NO, we measured spontaneous excitatory and inhibitory postsynaptic currents (EPSCs and IPSCs) from rat supraoptic nucleus neurones in slice preparations identified under a microscope using the whole-cell mode of the slice-patch-clamp technique. The NO donor, S-nitroso-N-acetylpenicillamine (SNAP), reversibly increased the frequency of spontaneous IPSCs mediated by GABAA receptors, without affecting the amplitude, indicating that NO potentiated IPSCs via a presynaptic mechanism. The NO scavenger, haemoglobin, suppressed the potentiation of IPSCs by SNAP. On the other hand, SNAP did not cause significant effects on EPSCs mediated by non-NMDA glutamate receptors. The membrane permeable analogue of cGMP, 8-bromo cGMP, caused a significant reduction in the frequency and amplitude of both IPSCs and EPSCs. The results suggest that NO preferentially potentiates the inhibitory synaptic inputs into supraoptic nucleus neurones by acting on GABA terminals in the supraoptic nucleus, possibly via a cGMP-independent mechanism. The potentiation may, at least in part, account for the inhibitory action of NO on the neural activity of supraoptic neurones.
The nectin-afadin complex is involved in the formation of cellcell junctions, such as adherens junctions (AJs) and tight junctions (TJs). Nectins are Ca
2+-independent immunoglobulinlike cell-cell adhesion molecules, whereas afadin is an intracellular nectin-binding protein that connects nectins to the cadherin-catenin system at AJs and to the claudin-zonaoccludens (ZO) protein system at TJs. Afadin -/-mice show embryonic lethality, resulting from impaired migration and improper differentiation of cells due to disorganization of cellcell junctions during gastrulation. However, it remains to be elucidated whether disruption of afadin affects apoptosis. In the present study, we first found that embryoid bodies derived from afadin-knockout embryonic stem (ES) cells contained many more apoptotic cells than those derived from wild-type ES cells. We also revealed that apoptosis induced by serum starvation or Fas-ligand stimulation was increased in cultured NIH3T3 cells when afadin or nectin-3 was knocked down. The nectinafadin complex was involved in the platelet-derived growth factor (PDGF)-induced activation of phosphatidylinositol 3-kinase (PI3K)-Akt signaling for cell survival. This complex was associated with PDGF receptor on the plasma membrane at cellcell adhesion sites. Thus, the nectin-afadin complex is involved in PDGF-induced cell survival, at least through the PI3K-Akt signaling pathway.
Supplementary material available online at
for the recruitment of afadin and the tyrosine phosphatase SHP-2 to the leading edge. SHP-2 was previously reported to tightly regulate the activation of PDGF receptor and its downstream signaling pathway for the formation of the leading edge. These results indicate that afadin has a novel role in PDGF-induced directional cell movement, presumably in cooperation with active Rap1 and SHP-2.Supplementary material available online at
Hemolytic uremic syndrome caused by Shiga toxin-producing Escherichia coli (STEC HUS) is a worldwide endemic problem and its pathophysiology is not fully elucidated. Here we tested whether the mannose-binding lectin (MBL2), an initiating factor of lectin complement pathway activation, plays a crucial role in STEC HUS. Using novel human MBL2 expressing mice (MBL2 KI) that lack murine Mbls (MBL2+/+Mbl1−/−Mbl2−/−), a novel STEC HUS model consisted of an intraperitoneal injection with Shiga toxin-2 (Stx-2) with or without anti-MBL2 antibody (3F8, intraperitoneal). Stx-2 induced weight loss, anemia, thrombocytopenia, and increased serum creatinine, free serum hemoglobin, and cystatin C levels, but a significantly decreased glomerular filtration rate all compared to control/sham mice. Immunohistochemical staining revealed renal C3d deposition and fibrin deposition in glomeruli in Stx-2 injected mice. Treatment with 3F8 completely inhibited serum MBL2 levels, and significantly attenuated Stx-2 induced renal injury, free serum hemoglobin levels, renal C3d and fibrin deposition, and preserved the glomerular filtration rate. Thus, MBL2 inhibition significantly protected against complement activation and renal injury induced by Stx-2. This novel mouse model can be used to study the role of complement, particularly lectin pathway-mediated complement activation, in Stx-2 induced renal injury.
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