Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The serotonin transporter (SERT) belongs to a family of sodium-chloride-dependent transporters responsible for uptake of amino acids and biogenic amines from the extracellular space. SERT represents a major pharmacological target in the treatment of several clinical conditions, including depression and anxiety. In the present study we have undertaken a mutational scanning of human SERT in order to identify residues that are responsible for individual differences among related monoamine transporters. One mutant, G100A, was inactive in transport. However, ligand binding affinity was similar to wild-type, suggesting that G100A amongst different possible SERT conformations is restrained to a binding conformation. We suggest that the main role of glycine-100 is to confer structural flexibility during substrate translocation. For the two single mutants, T178A and F263C, uptake rates and K(m) values were both several-fold higher than wild-type while binding affinities and inhibitory potencies decreased considerably for several drugs. Ion dependency increased and only at hyperosmotic concentrations were K(m) values partly restored. For the double mutant, T178A/F263C, shifts in uptake kinetics and ligand affinities, as well as ion dependencies, were drastic. Effects were synergistic compared to the corresponding single mutants. In conclusion, we suggest that mutating threonine-178 to an alanine and phenylalanine-263 to a cysteine mainly alter the overall uptake kinetics of SERT by affecting the conformational equilibrium of different transporter conformations.
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PMID:Mutational scanning of the human serotonin transporter reveals fast translocating serotonin transporter mutants. 1506 48

The early detection and appropriate treatment of brain ischemia is of paramount importance. The interstitial concentrations of neurotransmitter amino acids are often used as an index of neuronal injury. However, monitoring of non-neurotransmitter amino acids may be equally important. We have studied the behavior of 10 amino acids during K(+)-induced spreading depression (application of 70 mM KCl during 40 min) and global forebrain ischemia (two-vessel occlusion with hypotension during 20 min). The concentrations of glutamate, aspartate, taurine, GABA, glycine, and alanine, measured in the rat striatum by microdialysis, increased during both ischemia and spreading depression, whereas glutamine concentrations decreased in both cases. Only ischemia, but not spreading depression, led to enhanced release of serine, threonine, and asparagine. We thus conclude that an elevation in the interstitial concentrations of non-neurotransmitter amino acids is specific to deep ischemic injury to nervous tissue. We propose the monitoring of serine, asparagine, and threonine, together with excitatory amino acids, as an index of the degree of ischemic brain injury.
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PMID:Interstitial concentrations of amino acids in the rat striatum during global forebrain ischemia and potassium-evoked spreading depression. 1526 Jan 29

The effectiveness of natural antifreeze proteins in inhibiting the growth of a seed ice crystal seems to vary with protein size. Here we have made use of the extreme regularity of the beta-helical antifreeze protein from the beetle Tenebrio molitor to explore systematically the relationship between antifreeze activity and the area of the ice-binding site. Each of the 12-amino acid, disulfide-bonded central coils of the beta-helix contains a Thr-Xaa-Thr ice-binding motif. By adding coils to, and deleting coils from, the seven-coil parent antifreeze protein, we have made a series of constructs with 6-11 coils. Misfolded forms of these antifreezes were removed by ice affinity purification to accurately compare the specific activity of each construct. There was a 10-100-fold gain in activity upon going from six to nine coils, depending on the concentration that was compared. Activity was maximal for the nine-coil construct, which gave a freezing point depression of 6.5 C degrees at 0.7 mg/mL, but actually decreased for the 10- and 11-coil constructs. This small loss in activity might result from the accumulation of a slight mismatch between the spacing of the ice-binding threonine residues and the O atoms of the ice lattice.
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PMID:Enhancing the activity of a beta-helical antifreeze protein by the engineered addition of coils. 1536 48

In an attempt to dissect classical and operant conditioning in Drosophila melanogaster, we have isolated the gene for ribosomal S6 kinase II (S6KII). This enzyme is part of a family of serine-threonine kinases that in mammals have been implicated in the MAPK (mitogen-activated protein kinase) signaling cascade controlling (among other processes) synaptic plasticity (long-term potentiation/long-term depression) and memory formation. The human homolog rsk2 has been linked to mental retardation (Coffin-Lowry syndrome). Mutant analysis in Drosophila shows that S6KII serves different functions in operant place learning and classical (pavlovian) olfactory conditioning. Whereas in the null mutant only pavlovian olfactory learning is affected, a P-element insertion mutant reducing the amount of S6KII only affects operant place learning. A mutant lacking part of the N-terminal kinase domain and performing poorly in both learning tasks is dominant in the operant paradigm and recessive in the pavlovian paradigm. The behavioral defects in the pavlovian task can be rescued by the genomic S6KII transgene. Overexpression of S6KII in wild type has a dominant-negative effect on the operant task that is rescued by the null mutant, whereas in the pavlovian task overexpression may even enhance learning performance.
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PMID:The S6KII (rsk) gene of Drosophila melanogaster differentially affects an operant and a classical learning task. 1552 59

Cardioprotection by intermittent high-altitude (IHA) hypoxia against ischemia-reperfusion (I/R) injury is associated with Ca(2+) overload reduction. Phospholamban (PLB) phosphorylation relieves cardiac sarcoplasmic reticulum (SR) Ca(2+)-pump ATPase, a critical regulator in intracellular Ca(2+) cycling, from inhibition. To test the hypothesis that IHA hypoxia increases PLB phosphorylation and that such an effect plays a role in cardioprotection, we compared the time-dependent changes in the PLB phosphorylation at Ser(16) (PKA site) and Thr(17) (CaMKII site) in perfused normoxic rat hearts with those in IHA hypoxic rat hearts submitted to 30-min ischemia (I30) followed by 30-min reperfusion (R30). IHA hypoxia improved postischemic contractile recovery, reduced the maximum extent of ischemic contracture, and attenuated I/R-induced depression in Ca(2+)-pump ATPase activity. Although the PLB protein levels remained constant during I/R in both groups, Ser(16) phosphorylation increased at I30 and 1 min of reperfusion (R1) but decreased at R30 in normoxic hearts. IHA hypoxia upregulated the increase further at I30 and R1. Thr(17) phosphorylation decreased at I30, R1, and R30 in normoxic hearts, but IHA hypoxia attenuated the depression at R1 and R30. Moreover, PKA inhibitor H89 abolished IHA hypoxia-induced increase in Ser(16) phosphorylation, Ca(2+)-pump ATPase activity, and the recovery of cardiac performance after ischemia. CaMKII inhibitor KN-93 also abolished the beneficial effects of IHA hypoxia on Thr(17) phosphorylation, Ca(2+)-pump ATPase activity, and the postischemic contractile recovery. These findings indicate that IHA hypoxia mitigates I/R-induced depression in SR Ca(2+)-pump ATPase activity by upregulating dual-site PLB phosphorylation, which may consequently contribute to IHA hypoxia-induced cardioprotection against I/R injury.
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PMID:Role of dual-site phospholamban phosphorylation in intermittent hypoxia-induced cardioprotection against ischemia-reperfusion injury. 1563 15

Two-dimensional gel electrophoresis was used to assess differential protein expression between euthermic and hibernating states in heart of Myotis lucifugus. A hibernation-induced protein was identified by mass spectrometry as a thioredoxin peroxidase-like protein known as PAG. Western blotting confirmed up-regulation (>2-fold) and RT-PCR also revealed up-regulation (>5-fold) of pag mRNA. Cloning revealed a highly conserved sequence suggesting a conserved function for PAG. Oxidative stress markers, p-IkappaB-alpha (Ser 32) and p-HSP27 (Ser 78/82), were also up-regulated in heart and skeletal muscle during hibernation. Although there are selected increases in gene/protein expression during hibernation, general translation inhibition occurs as part of metabolic rate depression. This was confirmed by elevated levels of the inactive forms of the eIF2alpha (Ser 51) in both heart and skeletal muscle (2- to 5-fold higher than in euthermia) and the eEF2 (Thr 51) in skeletal muscle (a 15-fold increase). This study suggests that hibernators may use up-regulation of specific proteins to counteract oxidative stress.
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PMID:Up-regulation of a thioredoxin peroxidase-like protein, proliferation-associated gene, in hibernating bats. 1568 Sep 12

Neurokinin 1 (NK-1) receptor knockout mice showed behavioral responses similar to animals chronically treated with antidepressants. The aim of this study was to analyse, in NK-1 receptor knockout, the molecular modifications of signaling pathways involved in the pathophysiology of depression and antidepressant mechanism. We found, in total cell cytosol from the prefrontal/frontal cortex, hippocampus and striatum, a marked up-regulation of Ca(2+)-independent enzymatic activity and Thr(286) autophosphorylation of Ca(2+)/calmodulin-dependent protein kinase (CaMK) II. Similar changes in CaMKII regulation were previously observed in rats chronically treated with antidepressants. In striatum, up-regulation of the activity and phosphorylation of CaMKII was also found in the homogenate and synaptosomes. No major changes were observed in the Ca(2+)-dependent kinase activity, with the exception of homogenate from the prefrontal/frontal cortex. We also analysed the expression and phosphorylation of presynaptic proteins, which modulate synaptic vesicle trafficking and exocytosis, and found a marked decrease in synapsin I total expression and basal phosphorylation of Ser(603) (the phosphorylation site for CaMKII) in the prefrontal/frontal cortex. Accordingly, the Ca(2+)/calmodulin-dependent posthoc endogenous phosphorylation of synapsin I in the same area was increased. The knockout of NK-1 receptor had no consequences on the expression or phosphorylation levels of the transcription factor cAMP-responsive element-binding protein and its regulating kinase CaMKIV. However, phosphorylation of ERK1/2-mitogen-activated protein kinases was reduced in the hippocampus and striatum, again resembling an effect previously observed in antidepressant-treated rats. These results show similarities between NK-1 knockouts and animals chronically treated with antidepressants and support the putative antidepressant activity of NK-1 receptor antagonists.
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PMID:Changes in signaling pathways regulating neuroplasticity induced by neurokinin 1 receptor knockout. 1581 46

Synaptic plasticity is an important cellular mechanism that underlies memory formation. In brain areas involved in memory such as the hippocampus, long-term synaptic plasticity is bidirectional. Major forms of bidirectional plasticity encompass long-term potentiation (LTP), LTP reversal (depotentiation) and long-term depression (LTD). Protein kinases and protein phosphatases are important players in the induction of both LTP and LTD, and the serine/threonine protein phosphatase-1 (PP1), in particular, has emerged as a key phosphatase in these processes. The goal of the present study was to assess the contribution of PP1 to bidirectional plasticity and examine the impact of a partial inhibition of PP1 on LTP, LTD and depotentiation in the mouse hippocampus. For this, we used transgenic mice expressing an active PP1 inhibitor (I-1*) inducibly in forebrain neurons. We show that partial inhibition of PP1 by I-1* expression alters the properties of bidirectional plasticity by inducing a shift of synaptic responses towards potentiation. At low-frequency stimulation, PP1 inhibition decreases LTD in a frequency-dependent fashion. It favours potentiation over depression at intermediate frequencies and increases LTP at high frequency. Consistently, it also impairs depotentiation. These results indicate that the requirement of bidirectional plasticity for PP1 is frequency-dependent and that a broad range of plasticity is negatively constrained by PP1, a feature that may correlate with the property of PP1 to constrain learning efficacy and promote forgetting.
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PMID:Partial inhibition of PP1 alters bidirectional synaptic plasticity in the hippocampus. 1690 58

The glutamate receptor delta2 (GluRdelta2) is selectively expressed in cerebellar Purkinje cells and plays an important role in motor learning, motor coordination, and long-term depression. Delphilin is identified as a GluRdelta2-interacting protein, selectively expressed in Purkinje cell-parallel fiber synapses, and specifically interacts with the GluRdelta2 C-terminus via its PDZ domain. Here, surface plasmon resonance analyses showed that Delphilin PDZ bound to GluRdelta2 C-terminal peptide (DPDRGTSI), but not to its phosphopeptides (DPDRGphosphoTSI and DPDRGTphosphoSI). We showed the incorporation of phosphate into threonine at -2 (-2T) and serine at -1 (-1S) of GluRdelta2 C-terminus by cAMP-dependent protein kinase (PKA) in vitro. In the experiments using heterologous expression system, Delphilin coimmunoprecipitated with GluRdelta2 was dramatically decreased under the condition with forskolin and isobutylmethylxanthine, which led to cAMP-dependent phosphorylation by PKA. Thus, phosphorylation of -2T and/or -1S of GluRdelta2 C-terminus by PKA may regulate the binding of GluRdelta2 to its scaffolding protein, Delphilin.
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PMID:Binding of glutamate receptor delta2 to its scaffold protein, Delphilin, is regulated by PKA. 1702 46

We have identified YkbA from Bacillus subtilis as a novel member of the L-amino acid transporter (LAT) family of amino acid transporters. The protein is approximately 30% identical in amino acid sequence to the light subunits of human heteromeric amino acid transporters. Purified His-tagged YkbA from Escherichia coli membranes reconstituted in proteoliposomes exhibited sodium-independent, obligatory exchange activity for L-serine and L-threonine and also for aromatic amino acids, albeit with less activity. Thus, we propose that YkbA be renamed SteT (Ser/Thr exchanger transporter). Kinetic analysis supports a sequential mechanism of exchange for SteT. Freeze-fracture analysis of purified, functionally active SteT in proteoliposomes, together with blue native polyacrylamide gel electrophoresis and transmission electron microscopy of detergent-solubilized purified SteT, suggest that the transporter exists in a monomeric form. Freeze-fracture analysis showed spherical particles with a diameter of 7.4 nm. Transmission electron microscopy revealed elliptical particles (diameters 6 x 7 nm) with a distinct central depression. To our knowledge, this is the first functional characterization of a prokaryotic member of the LAT family and the first structural data on an APC (amino acids, polyamines, and choline for organocations) transporter. SteT represents an excellent model to study the molecular architecture of the light subunits of heteromeric amino acid transporters and other APC transporters.
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PMID:Functional and structural characterization of the first prokaryotic member of the L-amino acid transporter (LAT) family: a model for APC transporters. 1734 20


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