584 research outputs found
Targeting Acid-Sensing Ion Channels by Peptide Toxins
Acid-sensing ion channels (ASICs) are proton-gated ion channels that are highly expressed in the nervous system and play important roles in physiological and pathological conditions. They are also expressed in non-neuronal tissues with different functions. The ASICs rapidly respond to a reduction in extracellular pH with an inward current that is quickly inactivated despite the continuous presence of protons. Recently, protons have been identified as neurotransmitters in the brain. Until now, six different isoforms (ASIC1a, 1b, 2a, 2b, 3 and 4) in rodents have been discovered and they can be assembled into homotrimers or heterotrimers to form an ion channel. Peptide toxins targeting ASICs have been found from the venoms of spider Psalmotoxin-1 (PcTx1), sea anemones (APETx2 and PhcrTx1) and snakes (MitTx and mambalgins). They reveal different pharmacological properties and are selective blockers of ASICs, except for MitTx, which is a potent activator of ASICs. In this mini review, the structure, pharmacology and effects of peptide toxins on ASICs will be introduced and their therapeutic potentials for neurological and psychological diseases will be discussed
Modulation of Ionotropic Glutamate Receptors and Acid-Sensing Ion Channels by Nitric Oxide
Ionotropic glutamate receptors (iGluR) are ligand-gated ion channels and are densely expressed in broad areas of mammalian brains. Like iGluRs, acid-sensing ion channels (ASIC) are ligand (H+)-gated channels and are enriched in brain cells and peripheral sensory neurons. Both ion channels are enriched at excitatory synaptic sites, functionally coupled to each other, and subject to the modulation by a variety of signaling molecules. Central among them is a gasotransmitter, nitric oxide (NO). Available data show that NO activity-dependently modulates iGluRs and ASICs via either a direct or an indirect pathway. The former involves a NO-based and cGMP-independent post-translational modification (S-nitrosylation) of extracellular cysteine residues in channel subunits or channel-interacting proteins. The latter is achieved by NO activation of soluble guanylyl cyclase, which in turn triggers an intracellular cGMP-sensitive cascade to indirectly modulate iGluRs and ASICs. The NO modification is usually dynamic and reversible. Modified channels undergo significant, interrelated changes in biochemistry and electrophysiology. Since NO synthesis is enhanced in various neurological disorders, the NO modulation of iGluRs and ASICs is believed to be directly linked to the pathogenesis of these disorders. This review summarizes the direct and indirect modifications of iGluRs and ASICs by NO and analyzes the role of the NO-iGluR and NO-ASIC coupling in cell signaling and in the pathogenesis of certain related neurological diseases
The LAMOST Survey of Background Quasars in the Vicinity of the Andromeda and Triangulum Galaxies -- II. Results from the Commissioning Observations and the Pilot Surveys
We present new quasars discovered in the vicinity of the Andromeda and
Triangulum galaxies with the LAMOST during the 2010 and 2011 observational
seasons. Quasar candidates are selected based on the available SDSS, KPNO 4 m
telescope, XSTPS optical, and WISE near infrared photometric data. We present
509 new quasars discovered in a stripe of ~135 sq. deg from M31 to M33 along
the Giant Stellar Stream in the 2011 pilot survey datasets, and also 17 new
quasars discovered in an area of ~100 sq. deg that covers the central region
and the southeastern halo of M31 in the 2010 commissioning datasets. These 526
new quasars have i magnitudes ranging from 15.5 to 20.0, redshifts from 0.1 to
3.2. They represent a significant increase of the number of identified quasars
in the vicinity of M31 and M33. There are now 26, 62 and 139 known quasars in
this region of the sky with i magnitudes brighter than 17.0, 17.5 and 18.0
respectively, of which 5, 20 and 75 are newly-discovered. These bright quasars
provide an invaluable collection with which to probe the kinematics and
chemistry of the ISM/IGM in the Local Group of galaxies. A total of 93 quasars
are now known with locations within 2.5 deg of M31, of which 73 are newly
discovered. Tens of quasars are now known to be located behind the Giant
Stellar Stream, and hundreds behind the extended halo and its associated
substructures of M31. The much enlarged sample of known quasars in the vicinity
of M31 and M33 can potentially be utilized to construct a perfect astrometric
reference frame to measure the minute PMs of M31 and M33, along with the PMs of
substructures associated with the Local Group of galaxies. Those PMs are some
of the most fundamental properties of the Local Group.Comment: 26 pages, 6 figures, AJ accepte
Rapamycin Upregulates Connective Tissue Growth Factor Expression in Hepatic Progenitor Cells Through TGF-β-Smad2 Dependent Signaling
Rapamycin (sirolimus) is a mTOR kinase inhibitor and is widely used as an immunosuppressive drug to prevent graft rejection in organ transplantation currently. However, some recent investigations have reported that it had profibrotic effect in the progression of organ fibrosis, and its precise role in the liver fibrosis is still poorly understood. Here we showed that rapamycin upregulated connective tissue growth factor (CTGF) expression at the transcriptional level in hepatic progenitor cells (HPCs). Using lentivirus-mediated small hairpin RNA (shRNA) we demonstrated that knockdown of mTOR, Raptor, or Rictor mimicked the effect of rapamycin treatment. Mechanistically, inhibition of mTOR activity with rapamycin resulted in a hyperactive PI3K-Akt pathway, whereas this activation inhibited the expression of CTGF in HPCs. Besides, rapamycin activated the TGF-β-Smad signaling, and TGF-β receptor type I (TGFβRI) serine/threonine kinase inhibitors completely blocked the effects of rapamycin on HPCs. Moreover, Smad2 was involved in the induction of CTGF through rapamycin-activated TGF-β-Smad signaling as knockdown completely blocked CTGF induction, while knockdown of Smad4 expression partially inhibited induction, whereas Smad3 knockdown had no effect. Rapamycin also induced ROS generation and latent TGF-β activation which contributed to TGF-β-Smad signaling. In conclusion, this study demonstrates that rapamycin upregulates CTGF in HPCs and suggests that rapamycin has potential fibrotic effect in liver
Decreased Intrinsic Functional Connectivity of the Salience Network in Drug-Naïve Patients With Obsessive-Compulsive Disorder
Obsessive-compulsive disorder (OCD) patients have difficulty in switching between obsessive thought and compulsive behavior, which may be related to the dysfunction of the salience network (SN). However, little is known about the changes in intra- and inter- intrinsic functional connectivity (iFC) of the SN in patients with OCD. In this study, we parceled the SN into 19 subregions and investigated iFC changes for each of these subregions in 40 drug-naïve patients with OCD and 40 healthy controls (HCs) using seed-based functional connectivity resting-state functional magnetic resonance imaging (rs-fMRI). We found that patients with OCD exhibited decreased iFC strength between subregions of the SN, as well as decreased inter-network connectivity between SN and DMN, and ECN. These findings highlight a specific alteration in iFC patterns associated with SN in patients with OCD and provide new insights into the dysfunctional brain organization of the SN in patients with OCD
The Collapse of Neutron Stars in High-Mass Binaries as the Energy Source for the Gamma-Ray Bursts
The energy source has remained to be the great mystery in understanding of
the gamma-ray bursts (GRBs) if the events are placed at cosmological distances
as indicated by a number of recent observations. The currently popular models
include (1)the merger of two neutron stars or a neutron star and a black hole
binary and (2)the hypernova scenario of the collapse of a massive member in a
close binary. Since a neutron star will inevitably collapse into a black hole
if its mass exceeds the limit , releasing a total
binding gravitational energy of erg, we explore semi-empirically
the possibility of attributing the energy source of GRB to the accretion-
induced collapse of a neutron star (AICNS) in a massive X-ray binary system
consisting of a neutron star and a type O/B companion. This happens because a
significant mass flow of -- yr may be
transferred onto the neutron star through the Roche-lobe overflow and primarily
during the spiral-in phase when it plunges into the envelope of the companion,
which may eventually lead to the AICNS before the neutron star merges with the
core of the companion. In this scenario, a ``dirty'' fireball with a moderate
amount of beaming is naturally expected because of the nonuniformity of the
stellar matter surrounding the explosion inside the companion, and a small
fraction () of the energy is sufficient to create the observed GRBs.
In addition, the bulk of the ejecting matter of the companion star with a
relatively slow expansion rate may act as the afterglow. Assuming a
non-evolutionary model for galaxies, we estimate that the birthrate of the
AICNS events is about 2 per day within a volume to redshift for an
universe, consistent with the reported GRB rate.Comment: 4 pages, no figures, emulateapj.sty, to appear in ApJ Letters,
several paragraphs added, references added and update
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