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 effects of whole body dehydration (up to 40% of total body water lost) or anoxia exposure (up to 2 days under N2 gas) at 5 degrees C on tissue levels of adenosine 3'-5' cyclic monophosphate (cAMP) and the percentage of cAMP-dependent protein kinase present as the free catalytic subunit (PKAc), as well as the levels of the protein kinase C (PKC) second messenger, inositol 1,4,5-trisphosphate (IP3), were assessed in two anurans, the freeze-tolerant wood frog, Rana sylvatica, and the freeze-intolerant leopard frog, Rana pipiens. Dehydration of wood frogs resulted in a rapid elevation of liver cAMP and PKAc; cAMP was 3.4-fold greater than control values in animals that had lost 5% of total body water, whereas PKAc was elevated threefold in 20% dehydrated frogs. These results indicate protein kinase A mediation of the liver glycogenolysis and hyperglycemia that is induced by dehydration in this species. Skeletal muscle PKAc content also rose with dehydration but neither cAMP nor PKAc was affected by dehydration in leopard frog tissues. Anoxia exposure had different effects on signal transduction systems. PKAc was elevated after 1 h anoxia in R. sylvatica brain and was sustained over time but the enzyme was unaffected in other organs; by contrast, R. pipiens showed variable responses by PKAc to anoxia in three organs. Both species showed rapid (within 30 min) and large (3 to 7.8-fold) increases in IP3 in liver of anoxic frogs that decreased slowly with continued anoxia. IP3 also increased quickly in heart of anoxia-exposed wood frogs. This suggests that PKC may mediate various metabolic adjustments that promote hypoxia/anoxia resistance such as coordinating metabolic rate depression. A progressive rise in liver IP3 during dehydration in wood frogs (reaching fourfold higher than controls in 40% dehydrated animals) may also mediate similar hypoxia resistance adaptations under this stress since anurans experience progressive hypoxia due to increased blood viscosity when water loss reaches high values. The patterns of second messenger and PKAc changes in wood frog liver during dehydration closely parallel the changes seen in these same parameters during natural freezing suggesting that the freeze tolerance of selected terrestrially hibernating anurans may have evolved out of various anuran mechanisms of dehydration resistance.
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PMID:Second messenger and cAMP-dependent protein kinase responses to dehydration and anoxia stresses in frogs. 920 70

Saturation binding of [3H]cAMP to the regulatory subunit of cAMP-dependent protein kinase (PKA) was measured in the soluble fraction of brain samples, obtained at post-mortem, from suicides with a firm retrospective diagnosis of depression and individually matched controls. Suicides were subdivided into those who had been free of antidepressant drugs for at least 3 months and those in whom prescription of antidepressants was clearly documented. In antidepressant-free suicides, we found no significant differences in the number or affinity of [3H]cAMP binding sites in the five regions studied. In antidepressant-treated suicides however, Bmax values were lower in all regions, reaching statistical significance in parietal cortex and amygdala. Kd values for antidepressant-treated suicides were significantly higher in parietal cortex, temporal cortex and amygdala. These results suggest the regulatory subunit of PKA is unaltered in depression, but is influenced by antidepressant drugs.
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PMID:Brain [3H]cAMP binding sites are unaltered in depressed suicides, but decreased by antidepressants. 920 52

The mechanism underlying dopamine D1 receptor-mediated attenuation of glutamatergic synaptic input to nucleus accumbens (NAcc) neurons was investigated in slices of rat forebrain, using whole-cell patch-clamp recording. The depression by dopamine of EPSCs evoked by single-shock cortical stimulation was stimulus-dependent. Synaptic activation of NMDA-type glutamate receptors was critical for this effect, because dopamine-induced EPSC depressions were blocked by the competitive NMDA receptor antagonist D/L-2-amino-5-phosphonopentanoate (AP5). Application of NMDA also depressed the EPSC, and both this effect and the dopamine depressions were blocked by the A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), implicating adenosine release in the EPSC depression. A1 receptor agonists also depressed EPSCs by a presynaptic action, causing increased paired-pulse facilitation, but this was insensitive to AP5. Activation of D1 receptors enhanced both postsynaptic inward currents evoked by NMDA application and the isolated NMDA receptor-mediated component of synaptic transmission. The biochemical processes underlying the dopamine-induced EPSC depression did not involve either protein kinase A or the production of cAMP and its metabolites, because this effect was resistant to the protein kinase inhibitors H89 and H7 and the cAMP-specific phosphodiesterase inhibitor rolipram. We conclude that activation of postsynaptic D1 receptors enhances the synaptic activation of NMDA receptors in nucleus accumbens neurons, thereby promoting a transsynaptic feedback inhibition of glutamatergic synaptic transmission via release of adenosine. Unusually for D1 receptors, this phenomenon occurs independently of adenylyl cyclase stimulation. This process may contribute to the locomotor stimulant action of dopaminergic agents in the NAcc.
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PMID:A postsynaptic interaction between dopamine D1 and NMDA receptors promotes presynaptic inhibition in the rat nucleus accumbens via adenosine release. 920 11

Parallel fiber synapses onto Purkinje neurons in acute cerebellar slices undergo long-term depression (LTD) when presynaptic activity coincides with postsynaptic depolarization. These electrical inputs can be respectively replaced by nitric oxide (NO) and Ca2+ photolytically released inside the Purkinje neuron, showing that these two messengers are sufficient for LTD induction. NO acts via cGMP production because inhibitors of guanylate cyclase prevent LTD but can be circumvented by photoreleased cGMP combined with Ca2+ elevation. Three inhibitors of cGMP-dependent protein kinase, Rp-8Br-PET-cGMPS, KT5823, and a novel pseudosubstrate peptide, all block LTD. LTD induction permits <10 ms gap between NO release and Ca2+ elevation, whereas 200-300 ms is allowed between uncaged cGMP and Ca2+ increase. This surprising difference in timing precision can be explained either by tighter localization and faster decay of cGMP when generated by NO rather than uncaging, or by two independent coincidence detectors in series.
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PMID:Synergies and coincidence requirements between NO, cGMP, and Ca2+ in the induction of cerebellar long-term depression. 920 68

Sucrose gap recordings from the dorsal roots of isolated, hemisected frog spinal cords were used to determine the effects of metabotropic L-glutamate receptor activation on primary afferent terminals by (+/-)-1-amino-trans-1,3-cyclopentane-dicarboxylic acid (t-ACPD). Dorsal root potentials evoked by ventral root volleys were significantly reduced by t-ACPD (30 microM), as were GABA- and muscimol-induced afferent terminal depolarizations. The effects of t-ACPD on GABA-depolarizations depended upon activation of group I metabotropic glutamate receptors, i.e. the effects were blocked by the group I/II antagonist (RS)-alpha-methyl-4-carboxyphenylglycine, but not by the group II antagonist alpha-methyl-(2S,3S,4S)-alpha-(carboxycyclopropyl)-glycine or the group III antagonist alpha-methyl-(S)-2-amino-4-phosphonobutyrate and were mimicked by the group I agonist 3,5-dihydroxyphenylglycine but were not mimicked by the group III agonist (S)-2-amino-4-phosphonobutyrate. Increasing the intracellular concentration of 3'-5'-cyclic adenosine monophosphate with 8-bromo-cAMP, forskolin, and 3-isobutyl-1-methylxanthine significantly reduced GABA depolarizations, but the protein kinase inhibitors Rp-adenosine 3,5-cyclic monophosphothioate triethylamine and N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide did not alter t-ACPD's depression of GABA depolarizations. The actions of t-ACPD on GABA depolarizations were neither mimicked nor blocked by phorbol-12-myristate 13-acetate, thapsigargin, staurosporine, or arachidonic acid, presumptive indications that the effects of t-ACPD did not involve phosphoinositide hydrolysis, the release of Ca2+ from intracellular stores, or the formation of arachidonate. t-ACPD's effects on GABA depolarizations were blocked by 20 mM Mg2+, the broad spectrum L-glutamate antagonist kynurenate, and the selective N-methyl-D-aspartate antagonist D(-)-2-amino-5-phosphonovaleric acid, but not by the non-N-methyl-D-aspartate antagonist 6-cyano-7-nitroquinoxaline-2,3-dione. Low concentrations of N-methyl-D-aspartate (10 microM) mimicked the effect of t-ACPD on GABA responses. These results suggest that t-ACPD's depression of GABA depolarizations involves an indirect, three-stage mechanism that includes activation of Group I metabotropic glutamate receptors on interneurons and/or on afferent terminals, the release of L-glutamate from the latter structures, and the activation of N-methyl-D-aspartate receptors on primary afferent terminals. The depression of GABA depolarizations caused by the release of L-glutamate from afferent terminal and/or interneurons leads to a block of presynaptic inhibition (produced in the frog spinal cord by GABA) resulting in a positive feed-forward amplification of reflex transmission.
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PMID:Role of metabotropic glutamate receptors in the depression of GABA-mediated depolarization of frog primary afferent terminals. 933 Mar 69

The different cell types comprising cardiac muscle express one or more of the three isoforms (neuronal NOS, or nNOS; inducible NOS, or iNOS; and endothelial NOS, or eNOS) of nitric oxide synthase (NOS). nNOS is expressed in orthosympathetic nerve terminals and regulates the release of catecholamines in the heart. eNOS constitutively expressed in endothelial cells inhibits contractile tone and the proliferation of underlying vascular smooth muscle cells, inhibits platelet aggregation and monocyte adhesion, promotes diastolic relaxation, and decreases O2 consumption in cardiac muscle through paracrinally produced NO. eNOS is also constitutively expressed in cardiac myocytes from rodent and human species, where it autocrinally opposes the inotropic action of catecholamines after muscarinic cholinergic and beta-adrenergic receptor stimulation. iNOS gene transcription and protein expression are induced in all cell types after exposure to a variety of inflammatory cytokines. Aside from participating in the immune defense against intracellular microorganisms and viruses, the large amounts of NO produced autocrinally or paracrinally mediate the vasoplegia and myocardial depression characteristic of systemic immune stimulation and promote cell death through apoptosis. In cardiac myocytes, NO may regulate L-type calcium current and contraction through activation of cGMP-dependent protein kinase and cGMP-modulated phosphodiesterases. Other mechanisms independent of cGMP elevations may operate through interaction of NO with heme proteins, non-heme iron, or free thiol residues on target signaling proteins, enzymes, or ion channels. Given the multiplicity of NOS isoforms expressed in cardiac muscle and of the potential molecular targets for the NO produced, tight molecular regulation of NOS expression and activity at the transcriptional and posttranscriptional level appear to be needed to coordinate the many roles of NO in heart function in health and disease.
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PMID:Nitric oxide synthases and cardiac muscle. Autocrine and paracrine influences. 935 45

Using patch-clamp techniques we studied several aspects of intracellular GABA(A) and glycine Cl- current regulation in cortical and spinal cord neurons, respectively. Activation of PKA with a permeable analog of cyclic AMP (cAMP) produced a potentiation of the Cl- current activated with glycine, but not of the current induced with GABA. The inactive analog was without effect. Activation of PKC with 1 microM PMA reduced the amplitude of the GABA(A) and glycine currents. Internal application of 1 mM cGMP, on the other hand, had no effect on the amplitude of either current. The amplitude of these inhibitory currents changed slightly during 20 min of patch-clamp recording. Internal perfusion of the neurons with 1 microM okadaic acid, a phosphatase inhibitor, induced potentiation in both currents. The amplitude of GABA(A) and glycine currents recorded with 1 mM internal CaCl2 and 10 mM EGTA (10 nM free Ca2+) decayed by less than 30% of control. Increasing the CaCl2 concentration to 10 mM (34 microM free Ca2+) induced a transient potentiation of the GABA(A) current. A strong depression of current amplitude was found with longer times of dialysis. The glycine current, on the contrary, was unchanged by increasing the intracellular Ca2+ concentration. Activation of G proteins with internal FAl4- induced an inhibition of the GABA(A) current, but potentiated the amplitude of the strychnine-sensitive Cl- current. These results indicate that GABA(A) and glycine receptors are differentially regulated by activation of protein kinases, G proteins and Ca2+. This conclusion supports the existence of selectivity in the intracellular regulation of these two receptor types.
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PMID:Differential intracellular regulation of cortical GABA(A) and spinal glycine receptors in cultured neurons. 937 87

Lipopolysaccharide (LPS) plays a key role in the pathogenesis of sepsis. Cardiac function and the inotropic response to beta-adrenergic stimulation are impaired in sepsis. We hypothesized that LPS, in clinically relevant levels (1 ng/mL), directly depresses contractility and beta-adrenergic responses in cardiac myocytes. Cardiac myocytes were isolated from the left ventricle of adult rabbits using digestive enzymes (collagenase and protease). We depyrogenated the enzymes (LPS contamination lowered from 100 to 300 ng/mL to < 0.7 ng/mL) to minimize development of LPS tolerance during cell isolation. After 6 hours of incubation with 1 ng/mL LPS, there was a decrease in the extent of active cell shortening with no change in Ca2+ transients (measured with indo 1 fluorescence), indicating decreased myofilament responsiveness to Ca2+. This was related to NO pathways, since cGMP (a second messenger of NO) increased in cardiac myocytes and LPS effects were completely reversed with a 1 mmol/L NG-monomethyl-L-arginine (L-NMMA, a NO synthase inhibitor). LPS did not alter the intracellular Ca2+ response to beta-adrenergic stimulation with isoproterenol but attenuated the contractile response (maximal cell shortening, 15.5 +/- 1.0% versus 23.3 +/- 1.1% in control myocytes; P < .001). LPS attenuation of the contractile response to isoproterenol was restored completely by L-NMMA and almost completely restored (to 86% of the control response) by an inhibitor of cGMP-dependent protein kinase. We conclude that LPS depresses cardiac contractility and the contractile response to beta-adrenergic stimulation by a NO-cGMP-mediated decrease in myofilament responsiveness to Ca2+. The direct effects of low levels of LPS on cardiac myocytes may contribute to cardiac depression and hemodynamic decompensation during sepsis.
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PMID:Lipopolysaccharide depresses cardiac contractility and beta-adrenergic contractile response by decreasing myofilament response to Ca2+ in cardiac myocytes. 940 Mar 82

The nucleus accumbens is a forebrain region that mediates cocaine self-administration and withdrawal effects in animal models of cocaine dependence. Considerable evidence suggests an important role of dopamine D1 receptors in these effects. Using a combination of current-clamp recordings in brain slices and whole-cell patch-clamp recordings from freshly dissociated neurons, we found that nucleus accumbens neurons are less excitable in cocaine withdrawn rats because of a novel form of plasticity: reduced whole-cell sodium currents. Three days after discontinuation of repeated cocaine injections, nucleus accumbens neurons recorded in brain slices were less responsive to depolarizing current injections, had higher action potential thresholds, and had lower spike amplitudes. Freshly dissociated nucleus accumbens neurons from cocaine-pretreated rats exhibited diminished sodium current density and a depolarizing shift in the voltage-dependence of sodium channel activation. These effects appear to be related to enhanced basal phosphorylation of sodium channels because of increased transmission through the dopamine D1 receptor/cAMP-dependent protein kinase pathway. The effects of repeated cocaine administration were not mimicked by repeated injections of the local anesthetic lidocaine and were not observed in neurons within the motor cortex, indicating that they did not result from local anesthetic actions of cocaine. Because nucleus accumbens neurons are normally recruited to coordinate response patterns of movement and affect, the decreased excitability during cocaine withdrawal may be related to symptoms such as anergia, anhedonia, and depression.
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PMID:Whole-cell plasticity in cocaine withdrawal: reduced sodium currents in nucleus accumbens neurons. 1197 3

Nootropic agents are proposed to serve as cognition enhancers. The underlying mechanism, however, is largely unknown. The present study was conducted to assess the intracellular signal transduction pathways mediated by the nootropic nefiracetam in the native and mutant Torpedo californica nicotinic acetylcholine (ACh) receptors expressed in Xenopus laevis oocytes. Nefiracetam induced a short-term depression of ACh-evoked currents at submicromolar concentrations (0.01-0.1 microM) and a long-term enhancement of the currents at micromolar concentrations (1-10 microM). The depression was caused by activation of pertussis toxin-sensitive, G protein-regulated, cAMP-dependent protein kinase (PKA) with subsequent phosphorylation of the ACh receptors; in contrast, the enhancement was caused by activation of Ca(2+)-dependent protein kinase C (PKC) and the ensuing PKC phosphorylation of the receptors. Therefore, nefiracetam interacts with PKA and PKC pathways, which may explain a cellular mechanism for the action of cognition-enhancing agents.
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PMID:Nefiracetam modulates acetylcholine receptor currents via two different signal transduction pathways. 944 26


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