44 research outputs found
Regulation of dendritic spine morphology by an NMDA receptor-associated Rho GTPase-activating protein, p250GAP
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66364/1/j.1471-4159.2008.05335.x.pd
Lack of effect of bone marrow transplantation on airway hyperresponsiveness in an asthmatic
ABSTRACTBronchial asthma has been recognized as an inflammatory disorder in this past decade. This leads to an assumption that perfect control of inflammatory cells may cure this disease. However, herein we report on an asthmatic whose airway hyperresponsiveness (AHR) did not change after bone marrow transplantation (BMT). The concentrations of acetylcholine to produce a 20% fall in forced expiratory volume in 1 s 15 days before and 98 days after BMT were 900 and 480 μg/mL, respectively. Asthma treatment with beclo-methasone dipropionate and theophylline was continued before and after BMT and a conventional supporting therapy for BMT with cyclosporine A and methylprednisolone, followed by oral administration of tacrolimus hydrate alone inhibited graft-versus-host disease. Plasma interleukin (IL)-4, IL-5 and IgE, but not interferon-γ, levels decreased after BMT. Note that the second measurement of airway sensitivity was performed under systemic administration of tacrolimus. The presented case suggests that replacement of bone marrow-derived inflammatory cells is not enough to reverse once-established AHR. Hence, AHR and airway inflammation may develop independently in some part, but both need to be present for asthma to be present in this asthmatic
NMDAR2B tyrosine phosphorylation regulates anxiety-like behavior and CRF expression in the amygdala
<p>Abstract</p> <p>Background</p> <p>Anxiety disorders are a highly prevalent and disabling class of psychiatric disorders. There is growing evidence implicating the glutamate system in the pathophysiology and treatment of anxiety disorders, though the molecular mechanism by which the glutamate system regulates anxiety-like behavior remains unclear.</p> <p>Results</p> <p>In this study, we provide evidence suggesting that tyrosine phosphorylation of the NMDA receptor, an ionotropic glutamate receptor, contributes to anxiety-like behavior. The GluN2B subunit of the NMDA receptor is tyrosine-phosphorylated: Tyr-1472 is the major phosphorylation site. Homozygous knock-in mice that express a Tyr-1472-Phe mutant of GluN2B, which prevents phosphorylation of this site, show enhanced anxiety-like behavior in the elevated plus-maze test. Expression of corticotropin-releasing factor (CRF), which is important for the regulation of anxiety-like behavior, is increased in the amygdala of the knock-in mice. Furthermore, injection of CRF receptor antagonist attenuated the enhanced anxiety-like behavior of the knock-in mice. We also show that elevated plus-maze exposure simultaneously induced de-phosphorylation of Tyr-1472 and increased CRF expression.</p> <p>Conclusions</p> <p>These data suggest that Tyr-1472 phosphorylation on GluN2B is important for anxiety-like behavior by negative regulation of CRF expression in the amygdala.</p
Flecainide reduces ventricular arrhythmias via a mechanism that differs from that of β-blockers in catecholaminergic polymorphic ventricular tachycardia
AbstractBackgroundCatecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by episodic ventricular tachycardia induced by adrenergic stress. Although β-blockers are used as first-line therapy, their therapeutic effects are largely incomplete. Flecainide has recently been shown to modify the molecular defects in CPVT. The aim of this study was to investigate the effects of flecainide as an add-on to conventional therapy on exercise-induced ventricular arrhythmia and compare them with those of conventional therapy alone.MethodsThe study included 5 CPVT patients with a mutation in RYR2. They experienced episodic arrhythmic events despite conventional β-blocker therapy and were therefore given flecainide in addition. The effects of the addition of flecainide therapy on ventricular arrhythmia during exercise testing were compared with those of conventional therapy alone.ResultsBoth β-blockers alone and with additional flecainide increased the maximal workload attained at the onset of ventricular arrhythmia; however, only flecainide increased the sinus rate at the onset of ventricular arrhythmias. Furthermore, flecainide increased the exercise capacity by preventing exercise-induced arrhythmias. During a follow-up period of 17±2 months, 1 patient experienced recurrent arrhythmic episodes that were associated with noncompliance. All patients reported improvements in their ability to perform the activities of daily living.ConclusionFlecainide effectively reduced ventricular arrhythmias via a mechanism that differs from that of β-blockers in genotype-positive patients with CPVT. The specific effects of flecainide may be critical in the improvement noted in the patients' ability to perform daily activities
The Suzaku Observation of the Nucleus of the Radio-Loud Active Galaxy Centaurus A: Constraints on Abundances of the Accreting Material
A Suzaku observation of the nucleus of the radio-loud AGN Centaurus A in 2005
has yielded a broadband spectrum spanning 0.3 to 250 keV. The net exposure
times after screening were: 70 ks per X-ray Imaging Spectrometer (XIS) camera,
60.8 ks for the Hard X-ray Detector (HXD) PIN, and 17.1 ks for the HXD-GSO. The
hard X-rays are fit by two power-laws of the same slope, absorbed by columns of
1.5 and 7 * 10^{23} cm^{-2} respectively. The spectrum is consistent with
previous suggestions that the power-law components are X-ray emission from the
sub-pc VLBI jet and from Bondi accretion at the core, but it is also consistent
with a partial covering interpretation. The soft band is dominated by thermal
emission from the diffuse plasma and is fit well by a two-temperature VAPEC
model, plus a third power-law component to account for scattered nuclear
emission, jet emission, and emission from X-ray Binaries and other point
sources. Narrow fluorescent emission lines from Fe, Si, S, Ar, Ca and Ni are
detected. The Fe K alpha line width yields a 200 light-day lower limit on the
distance from the black hole to the line-emitting gas. Fe, Ca, and S K-shell
absorption edges are detected. Elemental abundances are constrained via
absorption edge depths and strengths of the fluorescent and diffuse plasma
emission lines. The high metallicity ([Fe/H]=+0.1) of the circumnuclear
material suggests that it could not have originated in the relatively
metal-poor outer halo unless enrichment by local star formation has occurred.
Relative abundances are consistent with enrichment from Type II and Ia
supernovae.Comment: Accepted for publication to ApJ. 22 pages, 11 figures (3 color). Uses
emulateapj5.sty. Grammatical errors corrected; some references update
Involvement of NMDAR2A tyrosine phosphorylation in depression‐related behaviour
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102200/1/embj2009300-sup-0001.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/102200/2/embj2009300.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/102200/3/embj2009300-sup-0003.pd
Phospholipase Cbeta4 and protein kinase Calpha and/or protein kinase CbetaI are involved in the induction of long term depression in cerebellar Purkinje cells.
Activation of the type-1 metabotropic glutamate receptor (mGluR1) signaling pathway in the cerebellum involves activation of phospholipase C (PLC) and protein kinase C (PKC) for the induction of cerebellar long term depression (LTD). The PLC and PKC isoforms that are involved in LTD remain unclear, however. One previous study found no change in LTD in PKCgamma-deficient mice, thus, in the present study, we examined cerebellar LTD in PLCbeta4-deficient mice. Immunohistochemical and Western blot analyses of cerebellum from wild-type mice revealed that PLCbeta1 was expressed weakly and uniformly, PLCbeta2 was not detected, PLCbeta3 was expressed predominantly in caudal cerebellum (lobes 7-10), and PLCbeta4 was expressed uniformly throughout. In PLCbeta4-deficient mice, expression of total PLCbeta, the mGluR1-mediated Ca(2+) response, and LTD induction were greatly reduced in rostral cerebellum (lobes 1-6). Furthermore, we used immunohistochemistry to localize PKCalpha, -betaI, -betaII, and -gamma in mouse cerebellar Purkinje cells during LTD induction. Both PKCalpha and PKCbetaI were found to be translocated to the plasmamembrane under these conditions. Taken together, these results suggest that mGluR1-mediated activation of PLCbeta4 in rostral cerebellar Purkinje cells induced LTD via PKCalpha and/or PKCbetaI
Neurotrophin-3 Is Involved in the Formation of Apical Dendritic Bundles in Cortical Layer 2 of the Rat
Apical dendritic bundles from pyramidal neurons are a prominent feature of cortical neuropil but with significant area specializations. Here, we investigate mechanisms of bundle formation, focusing on layer (L) 2 bundles in rat granular retrosplenial cortex (GRS), a limbic area implicated in spatial memory. By using microarrays, we first searched for genes highly and specifically expressed in GRS L2 at postnatal day (P) 3 versus GRS L2 at P12 (respectively, before and after bundle formation), versus GRS L5 (at P3), and versus L2 in barrel field cortex (BF) (at P3). Several genes, including neurotrophin-3 (NT-3), were identified as transiently and specifically expressed in GRS L2. Three of these were cloned and confirmed by in situ hybridization. To test that NT-3–mediated events are causally involved in bundle formation, we used in utero electroporation to overexpress NT-3 in other cortical areas. This produced prominent bundles of dendrites originating from L2 neurons in BF, where L2 bundles are normally absent. Intracellular biocytin fills, after physiological recording in vitro, revealed increased dendritic branching in L1 of BF. The controlled ectopic induction of dendritic bundles identifies a new role for NT-3 and a new in vivo model for investigating dendritic bundles and their formation
Emerging roles of ARHGAP33 in intracellular trafficking of TrkB and pathophysiology of neuropsychiatric disorders
Intracellular trafficking of receptor proteins is essential for neurons to detect various extracellular factors during the formation and refinement of neural circuits. However, the precise mechanisms underlying the trafficking of neurotrophin receptors to synapses remain elusive. Here, we demonstrate that a brain-enriched sorting nexin, ARHGAP33, is a new type of regulator for the intracellular trafficking of TrkB, a high-affinity receptor for brain-derived neurotrophic factor. ARHGAP33 knockout (KO) mice exhibit reduced expression of synaptic TrkB, impaired spine development and neuropsychiatric disorder-related behavioural abnormalities. These deficits are rescued by specific pharmacological enhancement of TrkB signalling in ARHGAP33 KO mice. Mechanistically, ARHGAP33 interacts with SORT1 to cooperatively regulate TrkB trafficking. Human ARHGAP33 is associated with brain phenotypes and reduced SORT1 expression is found in patients with schizophrenia. We propose that ARHGAP33/SORT1-mediated TrkB trafficking is essential for synapse development and that the dysfunction of this mechanism may be a new molecular pathology of neuropsychiatric disorders
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