Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neuronal cell death is in many cases regulated by competitive interactions between pro- and antiapoptotic proteins of the Bcl-2 family. In this study we have identified two splice variants of the rat proapoptotic molecule Bad, which differ in their carboxy-terminal regions. Both splice variants of Bad interacted with the antiapoptotic molecule Bcl-w as shown by yeast two-hybrid assay and by co-immunoprecipitation experiments from transfected cells. mRNA expression for the two variants of bad were detected in all neonatal and adult rat tissues tested. Overexpression of either of the two isoforms of Bad in nerve growth factor (NGF)-maintained sympathetic neurons by microinjection induced the cell death of these neurons, which was neutralized by co-expression of Bcl-w. Overexpression of Bcl-w in sympathetic neurons also counteracted death induced by NGF deprivation, which was not reduced by co-expression of either of the two Bad variants. The results suggest that Bcl-w, Bad-alpha, and Bad-beta may participate in the regulation of apoptosis in the sympathetic nervous system.
Mol Cell Neurosci 2001 Jan
PMID:Functional characterization of two splice variants of rat bad and their interaction with Bcl-w in sympathetic neurons. 1116 72

Sec1 molecules associate with t-SNAREs from the syntaxin family in a heterodimeric complex that plays an essential role in vesicle transport and membrane fusion. Neuronal rat n-Sec1 has an arch-shaped three-domain structure, which binds syntaxin 1a through contacts in domains 1 and 3. In both rat nSec1 and homologous squid s-Sec1, a potential effector-molecule binding-pocket is shaped by residues from domains 1 and 2 and is localized on the opposite side of the syntaxin 1a interaction site. Comparison of several crystal forms of unliganded neuronal squid Sec1 indicates a hinge region between domains 1 and 2 which allows domain 1 to rotate along a central axis. This movement could release syntaxin 1a upon interaction with a yet unspecified Sec1 effector molecule(s). The binding of an effector protein may also directly affect the conformation of the helical hairpin of domain 3, which contributes the other significant syntaxin 1a binding sites in the rat nSec1/syntaxin 1a complex structure but adopts multiple conformations in the unliganded s-Sec1 structures reported here.
J Mol Biol 2001 Feb 09
PMID:Crystal structures of neuronal squid Sec1 implicate inter-domain hinge movement in the release of t-SNAREs. 1117 89

Focal cerebral ischemia activates the nuclear protein poly(ADP-ribose) polymerase (PARP) by single DNA strand breaks which leads to energy depletion and cell necrosis. Deletion or inhibition of PARP protects against ischemic brain injury. Here we examined the neuroprotective effect of PJ34, a novel potent inhibitor of PARP in vitro and in vivo. Serum-free primary neuronal cultures derived from rat cortex (E15-17) and kept in culture for 10 days were exposed to oxygen glucose deprivation (OGD) in vitro. Neuronal injury was quantified by LDH release after 24 h. Pretreatment with 30-1000 nM PJ34 significantly protected from OGD-induced cell injury in a dose-dependent manner. For in vivo experiments SV/129 mice were treated with PJ34 (50 microg) by intraperitoneal injection 2 h before 1 h middle cerebral artery occlusion (MCAo) and again 6 h later. Twenty-three h after reperfusion ischemic injury was significantly decreased compared to vehicle-treated controls (infarct volume reduction of 40%, p<0.05). Similarly, in a rat model of MCAo (2 h occlusion followed by up to 22 h reperfusion), PJ34 administration (10 mg/kg i.v.) significantly reduced infarct size, and the effect of the drug was maintained even if it was given as late as 10 min prior to reperfusion time. PJ34 significantly protected in a 4 h, but not in a 24 h permanent occlusion model. In conclusion, PJ34, a novel, potent inhibitor of PARP exerts massive neuroprotective agents, with a significant therapeutic window of opportunity. The present work strengthens the concept that pharmacological PARP inhibition may be a suitable approach for the treatment of acute stroke in man.
Int J Mol Med 2001 Mar
PMID:Protective effects of PJ34, a novel, potent inhibitor of poly(ADP-ribose) polymerase (PARP) in in vitro and in vivo models of stroke. 1117 3

Neuronal death underlies the symptoms of many human neurological disorders, including Alzheimer's, Parkinson's and Huntington's diseases, stroke, and amyotrophic lateral sclerosis. The identification of specific genetic and environmental factors responsible for these diseases has bolstered evidence for a shared pathway of neuronal death--apoptosis--involving oxidative stress, perturbed calcium homeostasis, mitochondrial dysfunction and activation of cysteine proteases called caspases. These death cascades are counteracted by survival signals, which suppress oxyradicals and stabilize calcium homeostasis and mitochondrial function. With the identification of mechanisms that either promote or prevent neuronal apoptosis come new approaches for preventing and treating neurodegenerative disorders.
Nat Rev Mol Cell Biol 2000 Nov
PMID:Apoptosis in neurodegenerative disorders. 1125 64

We investigated the enzymatic source, cellular production, and functional importance of nitric oxide (NO) in rat diaphragm. Neuronal and endothelial isoforms of constituitive nitric oxide synthase (nc-NOS, ec-NOS) were identified by immunostaining. NOS activity measured in diaphragm homogenates averaged 5.1 pmol/min/mg. Passive diaphragm fiber bundles produced NO derivatives (NOx) at the rate of 0.9 pmol/min/mg as measured by the cytochrome c reduction assay; NO production was confirmed by photolysis/ chemiluminescence measurements. Endogenous NO depressed diaphragm contractile function. The force of submaximal contraction was increased by NOS inhibitors, an effect that was stable for up to 60 min and was reversed by NO donors. We conclude that diaphragm muscle fibers express nc-NOS, ec-NOS, or both; passive myocytes produce NOx; and NO or NO-derivatives inhibit force production by modulating excitation-contraction coupling.
Comp Biochem Physiol A Mol Integr Physiol 1998 Jan
PMID:Nitric oxide modulates excitation-contraction coupling in the diaphragm. 1125 87

Neuronal death is normal during nervous system development but is abnormal in brain and spinal cord disease and injury. Apoptosis and necrosis are types of cell death. They are generally considered to be distinct forms of cell death. The re-emergence of apoptosis may contribute to the neuronal degeneration in chronic neurodegenerative disease, such as amyotrophic lateral sclerosis and Alzheimer's disease, and in neurological injury such as cerebral ischemia and trauma. There is also mounting evidence supporting an apoptosis-necrosis cell death continuum. In this continuum, neuronal death can result from varying contributions of coexisting apoptotic and necrotic mechanisms; thus, some of the distinctions between apoptosis and necrosis are becoming blurred. Cell culture and animal model systems are revealing the mechanisms of cell death. Necrosis can result from acute oxidative stress. Apoptosis can be induced by cell surface receptor engagement, growth factor withdrawal, and DNA damage. Several families of proteins and specific biochemical signal-transduction pathways regulate cell death. Cell death signaling can involve plasma membrane death receptors, mitochondrial death proteins, proteases, kinases, and transcription factors. Players in the cell death and cell survival orchestra include Fas receptor, Bcl-2 and Bax (and their homologues), cytochrome c, caspases, p53, and extracellular signal-regulated protein kinases. Some forms of cell death require gene activation, RNA synthesis, and protein synthesis, whereas others forms are transcriptionally-translationally-independent and are driven by posttranslational mechanisms such as protein phosphorylation and protein translocation. A better understanding of the molecular mechanisms of neuronal cell death in nervous system development, injury and disease can lead to new therapeutic approaches for the prevention of neurodegeneration and neurological disabilities and will expand the field of cell death biology.
Int J Mol Med 2001 May
PMID:Neuronal cell death in nervous system development, disease, and injury (Review). 1129 6

Hypoxia-ischemia (HI) in the newborn can lead to a variety of sensorimotor abnormalities, including movement and posture disorders. Striatal neurons undergo necrosis after HI in piglets, but mechanisms for this neuronal death are not understood. We tested the hypothesis that Na,K-ATPase is defective in striatum early after HI. Piglets (1 week old) were subjected to 30 min hypoxia (arterial oxygen saturation 30%) and then 7 min of airway occlusion (oxygen saturation 5%), producing asphyxic cardiac arrest. Animals were resuscitated and recovered for 3, 6, 12, and 24 h, respectively. Neuronal necrosis in the striatum is progressive [14]. Na,K-ATPase activity (percent of control) was 60, 98, 51, and 54% at 3, 6, 12, and 24 h after HI, respectively. Intrastriatal differences in enzyme activity were detected histochemically, with the putamen showing greater loss of Na,K-ATPase activity than caudate after 12 h recovery. Immunoblotting showed that the levels of the alpha(3) isoform (localized exclusively to neurons) were 85, 115, 101, and 79% of sham control at 3, 6, 12, and 24 h, respectively. Levels of beta(1), the predominant beta isoform, were similar to alpha(3), while levels of the alpha(1) subunit, the catalytic isoform found in neurons and glia, were 182, 179, 226, and 153% at the same recovery times. We conclude that early inactivation of Na,K-ATPase function participates in the pathogenesis of striatal neuron necrosis, but that loss of enzyme function early after HI is not caused by depletion of composite alpha/beta subunits.
Brain Res Mol Brain Res 2001 Mar 31
PMID:Failure to sustain recovery of Na,K-ATPase function is a possible mechanism for striatal neurodegeneration in hypoxic-ischemic newborn piglets. 1129 35

UDP-glucuronosyltransferases (UGTs) form a multigenic family of enzymes involved in the biotransformation and elimination of numerous endo- and xenobiotic compounds. Beside the diverse UGT isoforms present in the liver as well as in other tissues, the UGT2A1 isoform, also called olfactory UGT, was initially thought to be expressed in the nasal epithelium only. In this work, we demonstrate the UGT2A1 mRNA expression in the olfactory bulb, using in situ hybridization and quantitative reverse transcription-polymerase chain reaction (RT-PCR) techniques. Within the epithelium, UGT2A1 mRNA is mainly found in the sustentacular cells and to a lesser extent in Bowman's gland cells. Moreover, in situ hybrization staining reveals UGT2A1 mRNA expression in the olfactory sensory neuron nuclei. Neuronal localization of UGT2A1 mRNA within the olfactory bulb is mainly found in the deeper granular cells. The development of the quantitative multistandard RT-PCR method firstly required characterization of the mouse Ugt2A1 cDNA by rapid amplification of cDNA ends (RACE)-PCR. UGT2A1 mRNA levels appear quantitatively six-fold lower in the olfactory bulb than in the epithelium, in both the rat and mouse. The expression of UGT2A1 in the olfactory bulb, which directly connects the nasal epithelium to the brain, emphasizes the potential role of this enzyme in the protection of the brain against airborne hazardous chemicals.
Brain Res Mol Brain Res 2001 May 20
PMID:Rat olfactory bulb and epithelium UDP-glucuronosyltransferase 2A1 (UGT2A1) expression: in situ mRNA localization and quantitative analysis. 1137 59

Neuronal degeneration after traumatic injury to the central nervous system (CNS) can be reduced by active immunization or passive transfer of T cells against CNS-associated myelin antigens. We propose that a protective autoimmunity is evoked by CNS insult when non-immunological local protective mechanisms cannot adequately buffer the injury-induced toxicity. The ability of a particular strain to develop a protective autoimmune response appears to be inversely related to its susceptibility to autoimmune disease. We also propose that vaccination with specific CNS-derived'safe' (non-pathogenic) peptides after traumatic CNS insult, and possibly at any stage of chronic neurodegenerative disease, can be used to boost the protective autoimmunity and thereby to reduce further injury-induced damage. Such therapeutic vaccination ensures that the augmented beneficial autoimmunity will be free of accompanying disease.
Trends Mol Med 2001 Jun
PMID:Protective autoimmunity: regulation and prospects for vaccination after brain and spinal cord injuries. 1137 14

In the past several years there has been significant progress made on the biophysics of neurotransmitter transporters, leading to the proposal of new models of substrate and ion permeation across membranes. Questions arising from these studies are as follows: How are substrate uptake and substrate-induced current related? Where and how does substrate-ion coupling occur? What is the functional significance of the coupled and uncoupled currents? Because of a long-standing interest and collaboration, and because of their importance for normal function and disease, the authors have focused on the properties of human norepinephrine and serotonin transporters, using other clones and mutations as specific needs arise. It has been know for decades that hNETs (human norepinephrine transporters) clear NE+ (norepinephrine) following its release in peripheral sympathetic and central noradrenergic synapses. Neuronal activity influences NE+ uptake, so one is also interested in the acute regulation of hNET. To study these problems, hNET-expressing cells have been developed that are suitable for patch clamp, radioligand uptake, biochemistry, and transiently expressed clones for structure-function analysis, and new protocols have been designed combining patch-clamp, microamperometry, Ca2+ imaging, and native catecholamine transporter preparations to study transporters in whole cells and isolated patches. Using these methods, Na-dependent, NE+-induced hNET currents that are blocked by cocaine and antidepressants, channel modes of NE+ conduction, voltage-dependent uptake coupled to NE+-induced ion channel activity, PKC (phosphokinase C) regulation of NE+ uptake, and transporter modulation by [Ca2+]i have all been discovered. There is also provocative new data on other transporters in this family, such as Li/Na mole fraction experiments in the Drosophila serotonin transporters and sided enkephalin block in proline transporters. These studies have led one to postulate the existence of a narrow pore within transporters through which the substrate (NE+ or serotonin, 5HT+) and other ions (principally Na+) pass. It is hypothesized that the pore resides in an oligomeric structure and that separate gene products of hNET or hSERT (human serotonin transporters) come together to form a channel.
Mol Membr Biol
PMID:Serotonin and norepinephrine transporters: possible relationship between oligomeric structure and channel modes of conduction. 1139 11


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