UMLS:C0011570 - FACTA Search

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Query: UMLS:C0011570 (depression)
172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tachykinins belong to an evolutionarily conserved family of peptide neurotransmitters. The mammalian tachykinins include substance P, neurokinin A and neurokinin B, which exert their effects by binding to specific receptors. These tachykinin receptors are divided into three types, designated NK1, NK2 and NK3, respectively. Tachykinin receptors have been cloned and contain seven segments spanning the cell membrane, indicating their inclusion in the G-protein-linked receptor family. The continued development of selective agonists and antagonists for each receptor has helped elucidate roles for these mediators, ranging from effects in the central nervous system to the perpetuation of the inflammatory response in the periphery. Various selective ligands have shown both inter- and intraspecies differences in binding potencies, indicating distinct binding sites in the tachykinin receptor. The interaction of tachykinin with its receptor activates Gq, which in turn activates phospholipase C to break down phosphatidyl inositol bisphosphate into inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 acts on specific receptors in the sarcoplasmic reticulum to release intracellular stores of Ca2+, while DAG acts via protein kinase C to open L-type calcium channels in the plasma membrane. The rise in intracellular [Ca2+] induces the tissue response. With an array of actions as diverse as that seen with tachykinins, there is scope for numerous therapeutic possibilities. With the development of potent, selective non-peptide antagonists, there could be potential benefits in the treatment of a variety of clinical conditions, including chronic pain, Parkinson's disease, Alzheimer's disease, depression, rheumatoid arthritis, irritable bowel syndrome and asthma.
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PMID:Tachykinins: receptor to effector. 892 4

Animal survival during severe hypoxia and/or anoxia is enhanced by a variety of biochemical adaptations including adaptations of fermentative pathways of energy production and, most importantly, the ability to sharply reduce metabolic rate by 5-20 fold and enter a hypometabolic state. The biochemical regulation of metabolic arrest is proving to have common molecular principles that extend across phylogenetic lines and that are conserved in different types of arrested states (not only anaerobiosis but also estivation, hibernation, etc.). Our new studies with anoxia-tolerant vertebrates have identified a variety of regulatory mechanisms involved in both metabolic rate depression and in the aerobic recovery process using as models the freshwater turtle Trachemys scripta elegans and garter snakes Thamnophis sirtalis parietalis. Mechanisms include: 1) post-translational modification of cellular and functional proteins by reversible phosphorylation and changes in protein kinase (PKA, PKC) and/or phosphatase activities to regulate this, 2) reversible enzyme binding associations with subcellular structural elements, 3) differential gene expression and/or mRNA translation producing new mRNA variants and new protein products, 4) changes in protease activity, particularly the multicatalytic proteinase complex, and 5) both constitutive and anoxia-induced modifications to cellular antioxidant systems to deal with oxidative stress during the anoxic-aerobic transition of recovery.
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PMID:Metabolic adaptations supporting anoxia tolerance in reptiles: recent advances. 893 40

We studied the effect of the adenylate cyclase activator forskolin, of protein kinase C-activating phorbol esters and of prolonged preganglionic input activation on the inhibitory response of the perfused superior cervical ganglion of the cat to exogenous met-enkephalin (Met-ENK). Met-ENK inhibited, in a concentration-dependent manner, the postganglionic compound action potential evoked by cervical sympathetic trunk stimulation. The inhibition was reversible, was blocked by naloxone as well as by pertussis toxin and showed no homologous desensitization in the concentration range 0.01-10 microM. Pretreatment of the ganglion with 4 beta-phorbol 12,13-dibutyrate or 4 beta-phorbol 12,13-diacetate depressed the Met-ENK response for several hours, while pretreatment with forskolin had no effect. This action of phorbol esters was prevented by the protein kinase inhibitor H-7 but not by the calmodulin antagonist W-7 or the protein kinase A inhibitor HA 1004 and was calcium-dependent. Recovery of the response from the depression produced by phorbol esters was not affected by a protein synthesis inhibitor. A 40 Hz 20 min stimulus train to the cervical sympathetic trunk mimicked the effect of phorbol esters, depressing for several hours the inhibition produced by Met-ENK. Stimulus trains of duration shorter than 5 min or frequency lower than 5 Hz were ineffective. This effect of prolonged preganglionic stimulation occurred even when the stimulus train was delivered during complete block of nicotinic and muscarinic ganglionic transmission but was lost when the stimulus train was delivered during perfusion with calcium-free Krebs. The protein kinase inhibitor H-7 prevented the depression of the Met-ENK response by the train, while W-7 and HA 1004 had no effect. These findings suggest that, in the superior cervical ganglion of the cat, a kinase, activated by phorbol esters and inhibited by H-7, exerts a long-term control of the ganglion cell responsiveness to opiate receptor activation. A similar mechanism can be synaptically activated by a non-cholinergic transmitter, released by the preganglionic axons during prolonged, high frequency, activity.
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PMID:Long-term depression of a sympathetic ganglionic response to opioids by prolonged synaptic activity and by phorbol esters. 896 46

Modulation of L-type calcium channels by the five cloned muscarinic receptors was studied by expression of the receptors in NIH 3T3 cells. Application of acetylcholine (ACh) to cells transfected with m1-m5 resulted in a reduction in the L-type calcium current amplitude. Elevations in intracellular cAMP concentrations induced by 8-bromo-cAMP or forskolin resulted in no discernible change in the L-type calcium current. In addition, treatment with Rp-adenosine 3',5'-cyclic monophosphothioate triethylamine (Rp-cAMPS), a protein kinase A (PKA) inhibitor, had no effect on the L-type currents. Conversely, application of phorbol dibutyrate, an activator of protein kinase C (PKC) or 8-bromo-cGMP, an activator of cGMP-dependent protein kinase (PKG), reduced the calcium currents. Incubation of the cells with KT5823, an inhibitor of PKG, resulted in a reduction of the response to 8-bromo-cGMP. The ACh-induced depression of L-type calcium current amplitude was sensitive to pertussis toxin (PTX) in cells transfected with the m2 or m4 receptor subtype. The m2-muscarinic-receptor-induced inhibition of the L-type calcium current was attenuated by preincubation of the cells with 8-bromo-cAMP and was unaffected by KT5823 or by calphostin C. The m1-muscarinic-receptor-induced inhibition of the L-type calcium conductance was insensitive to PTX treatment. However, the m1-induced response was blocked by preincubation of the cells with calphostin C. The present data indicate that the m2 (and possibly also the m4) muscarinic receptors inhibit the L-type calcium conductance by a reduction in cAMP concentration and that the m1 (and possibly also the m3 and m5) muscarinic receptors inhibit the L-type calcium channel via activation of PKC.
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PMID:Inhibition of the L-type calcium channel by the five muscarinic receptors (m1-m5) expressed in NIH 3T3 cells. 900 Apr 30

The effect of cisplatin and the new drug cycloplatam (amine (cyclopentylamine)-S-(-)-malatoplatinum (II)) on protein kinase C (PKC) activity and Ca(2+)-dependent binding of PKC to T lymphocytes membranes was studied in vivo and in vitro. At first, the effect of the drugs on PKC activity of intact and activated lymphocytes was studied in vivo. In 48 hours after intraperitoneal injection of mice with therapeutic doses of the drugs, PKC activity of intact lymphocytes was differentially affected. Cisplatin did not practically alter the enzyme activity, whereas cycloplatam inhibited the PKC activity by 37% versus control. In lymphocytes activated by mouse P-388 leukemia cells in vivo, the drugs caused almost complete suppression of PKC activity and Ca(2+)-dependent binding of the enzyme to the membranes. The drugs were effective in intact cells. After incubation of intact lymphocytes in vitro for 24 hours with cisplatin or cycloplatam (10(-5)M), PKC activity was increased 1.62- and 1.35-fold, respectively, versus control. Ca(2+)-dependent binding of the enzyme to the membranes was also increased 1.61- and 1.36-fold by cisplatin and cycloplatam, respectively. On the contrary, at 10(-4) M concentration under similar conditions, the drugs did not affect the PKC activity of the lymphocytes. Furthermore, cycloplatam, unlike cisplatin, reduced the PKC binding to cellular membranes by 31%. The mechanisms of the drugs effects on PKC activity are suggested. The data indicate that increase or decrease of PKC activity induced by the drugs cause stimulation or depression of functional activity of T lymphocytes, respectively. Thus, the membrane-bound PKC can play the key role in initiation and development of immunomodulatory effects of cisplatin and cycloplatam.
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PMID:[Effect of anti-tumor agents cisplatin and cycloplatam on membrane protein kinase C activity in murine T-lymphocytes]. 901 Dec 34

Spreading depression (SD) is a propagating depolarization of populations of neurons induced by intense electrical, chemical, or mechanical stimulation, which has been proposed to be an important mechanism in the aura of migraine. SD is characterized by a transient loss of synaptic transmission and thus may involve signal transduction mechanisms known to modulate synaptic strength. To examine the underlying pathophysiological molecular mechanisms of SD, we analyzed the regulation of eight protein kinase C (PKC) isoforms by immunoblot during SD induced by a high-intensity stimulus of synaptic afferents in the CA1 region of hippocampal slices. We observed a downregulation of the conventional (alpha, beta I, beta II, gamma) and the novel (delta, epsilon, eta) PKC isoforms in SD, but no change in the atypical isozyme (zeta). The coordinate downregulation of multiple PKC isoforms may be important in the functional depression of neuronal activity in SD. In contrast, the atypical zeta, and its constitutively active fragment PKM zeta, is a specific PKC isozyme that has been implicated in the maintenance of long-term potentiation (LTP) and long-term depression (LTD), widely studied models for the mechanism of memory. The stability of PKC zeta and PKM zeta in SD indicates that a molecular mechanism for the maintenance of LTP/ LTD is relatively resistant to alterations that occur during pathophysiologically large ionic fluxes. This result could help to explain the retention of information stored in the cortex despite the massive release of excitatory neurotransmitter and neuronal depolarization that may occur during the migrainous aura.
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PMID:Differential downregulation of protein kinase C isoforms in spreading depression. 901 75

Protein kinase C was purified to homogeneity from liver of the anoxia-tolerant turtle (Trachemys scripta elegans). Two isozymes were present and were identified as PKC alpha and PKC beta by hydroxylapatite chromatography and cross-reaction with specific antibodies to the mammalian isozymes. Kinetic characterization of the isozymes showed that both required phospholipids and Ca2+ for activation and both were inhibited by low concentrations of PKC inhibitors. The PKC alpha was activated more strongly by phosphatidylinositol and lysophosphatidylinositol compared with PKC beta. Treatment with trypsin did not activate turtle PKC isozymes, but generated inactive PKC beta, whereas PKC alpha was resistant to inactivation. Anoxia exposure of turtles in vivo, via submergence in N2-gassed water at 7 degrees C, altered the activity and subcellular distribution of PKC in liver. After 1 hr of anoxic exposure at 7 degrees C, the activity of membrane-bound PKC had increased by 2.4-fold and represented a translocation of 40% of PKC beta and more than 80% of PKC alpha from the cytosol to the membrane-associated fraction. With longer submergence, however, membrane-bound PKC activity was suppressed again. This two-phase response to anoxia by PKC suggests that an activation of PKC, through its translocation to the membrane, is important in mediating the initial metabolic responses to submergence, which include an activation of glycogenolysis during the hypoxia transition period. With sustained anoxia exposure, the subsequent reduction of PKC activity may be part of the overall mechanism of metabolic rate depression that allows endurance of prolonged anoxia.
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PMID:Liver protein kinase C isozymes: properties and enzyme role in a vertebrate facultative anaerobe. 902 85

The whole-cell configuration of the patch-clamp technique was used to study the involvement of protein kinase C (PKC) in the modulation of K+ channels in cultured microglia from newborn rats. We previously showed that 24-hr treatments with interferon-gamma (IFN-gamma) induce an increase of inward-rectifying (IR) and outward-rectifying (OR) current density and that the effect on OR was shared by bacterial lipopolysaccharide (LPS) (Visentin et al.: J Neurosci Res 42:439-451, 1995). In the present study, IFN-gamma (1-500 U/ml, 24 hr) enhanced IR current density up to threefold. The IFN-gamma effect was not detectable after shorter treatments (1-5 hr) and was abrogated by a protein synthesis inhibitor. The PKC activator phorbol myristate acetate (PMA) also increased IR current density, whereas the inactive alpha-4 isoform was ineffective. When IFN-gamma and PMA were co-applied, the effect was more than additive. Among the PKC inhibitors tested, staurosporine (STA)-but not calphostin C (CALP)-abolished the effect of IFN-gamma and of PMA and antagonized only partially that of co-applied IFN-gamma and PMA. OR currents were affected by treatment (24 hr) with PKC modulating agents in an opposite fashion. PMA depressed OR currents in control and in IFN-gamma (or LPS) treated cultures, even when added after pretreatment (with LPS) that was long enough to enhance OR channel expression. Both STA and CALP enhanced OR density in resting and IFN-gamma-stimulated cells but did not counteract the depressing effect of PMA. In conclusion, our data on IR suggest a relationship between the IFN-gamma effect on current density and PKC activation. However, we cannot conclude with certainty that IFN-gamma acts through PKC activation. Our data on OR support an inverse relationship between PKC activation and OR current density. Nevertheless, the lack of effect of PKC inhibitors on PMA-induced OR depression suggests that PMA may, in this case, act on a target different from PKC.
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PMID:Protein kinase C involvement in the resting and interferon-gamma-induced K+ channel profile of microglial cells. 903 45

The effects of cis-unsaturated free fatty acids such as linoleic and linolenic acid on ACh-evoked currents were examined using normal and mutant nicotinic acetylcholine (ACh) receptors lacking protein kinase C (PKC) phosphorylation sites on the alpha and delta subunits expressed in Xenopus oocytes. These free fatty acids reduced ACh-gated channel currents during treatment and to a greater extent in Ca2+-free extracellular solution. After treatment, the currents were enhanced as the drug was washed out, but this effect was not observed in the absence of extracellular Ca2+. Linolenic acid was more potent of the current enhancement (300% of the control) than linoleic acid (190% of the control). The current enhancement induced by these free fatty acids was inhibited by the selective PKC inhibitor, GF109203X, while the current depression was not affected. Furthermore, these lipids decreased ACh-evoked currents in mutant ACh receptors to the same extent as in normal ACh receptors, but never enhanced the currents. These results indicate that linoleic and linolenic acid have biphasic actions on ACh receptor currents; a short-term depression and a long-term enhancement. The short-term depression may be due to an interaction with the ACh receptor channels, presumably at Ca2+ binding sites. The long-lasting enhancement appears to result from Ca2+-dependent PKC activation followed by PKC phosphorylation of the ACh receptors.
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PMID:Short-term depression and long-term enhancement of ACh-gated channel currents induced by linoleic and linolenic acid. 909 12

The parallel fibers (PFs) of the dorsal cochlear nucleus (DCN) molecular layer use glutamate as a neurotransmitter. Although metabotropic glutamate receptors (mGluRs) have been identified on cells postsynaptic to the PFs, little is known about the effects of mGluR activation in PF synaptic transmission in the DCN. To investigate these effects, PF-evoked field potentials were recorded from the DCN in guinea pig brain stem slice preparations. The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated components of the field response were reversibly depressed by bathing the slice in the mGluR agonists (+/-)-aminocyclopentane-1,3-dicarboxylic acid (trans-ACPD) or (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD]. A similar depression was produced by the mGluR1/5 agonist (RS)-3,5-dihydroxyphenylglycine, but not by the mGluR2/3 agonist (2S,1'S,2'S)-2-(carboxycyclopropyl)glycine or by the mGluR4/6/7/8 agonist L(+)-2-amino-4-phosphonobutyric acid. In addition to the AMPA component, an N-methyl-D-aspartate (NMDA) receptor-dependent component of the field potentials could be identified when the slices were bathed in a low magnesium solution. Under these conditions, the ACPD-induced depression of the AMPA component did not completely recover, whereas the depression of the NMDA component usually recovered and potentiated in some slices. Intracellular recordings of PF-evoked responses were obtained to ascertain which neuronal populations were affected by mGluR activation. Activation of mGluRs produced a reversible depression of PF-evoked responses in cartwheel cells that was not accompanied by any changes in paired-pulse facilitation. The PF-evoked responses recorded from pyramidal cells were unaffected by mGluR activation. Both cell types exhibited a reversible depolarization during (1S,3R)-ACPD application. Subsequent experiments explored the involvement of protein kinases in mediating the effects of mGluRs. The protein kinase C (PKC) activator phorbol-12,13-diacetate partially inhibited the mGluR-mediated depression of the field response; however, the PKC inhibitor 2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)-maleimide or the protein kinase A inhibitor N-[2-((p-bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamide had little effect on the actions of (1S,3R)-ACPD. These results demonstrate that functional mGluRs are present at PF synapses and are capable of modulating PF synaptic transmission in the DCN.
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PMID:Evidence for functional metabotropic glutamate receptors in the dorsal cochlear nucleus. 911 43

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