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

Although phosphoinositide-specific phospholipase C (PLC) is involved in signal transduction mechanisms of the myocardial cell. very little is known about its status in congestive heart failure (CHF). We have examined the PLC activity in sarcolemmal and cytosolic fractions isolated from the viable left ventricle of rats at 8 weeks (moderate stage of CHF) and 16 weeks (severe stage of CHF) after occlusion of the left anterior descending coronary artery; the hypertrophied right ventricle was used for comparison. At 8 weeks, the hydrolysis of phosphatidylinositol 4,5-bisphosphate by sarcolemmal PLC was reduced by 37% of sham control values only in the left ventricle, whereas at 16 weeks, PLC-mediated hydrolysis was depressed in both left and right ventricles by 25% and 30%, respectively. The hydrolysis of phosphatidylinositol 4-monophosphate (PIP) was reduced by 25% of control value only in the severely failing left ventricle, while the phosphatidylinositol (PI) hydrolysis remained unaltered. Kinetic studies of PLC activity in the left ventricle showed a depression of V(max) at moderate and severe failure stages, whereas the affinity for the substrate was increased in the left ventricle at 8 weeks and decreased in the right ventricle at 16 weeks. The only difference observed between experimental and control groups at the cytosolic level, was a significant enhancement of PLC activity in the severely failing left ventricle when PIP was given as a substrate, and in the corresponding right ventricle when PI was the substrate. The results of this study identify time-related defects in sarcolemmal PLC in right and left ventricles during the development of CHF due to myocardial infarction.
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PMID:Identification of changes in cardiac phospholipase C activity in congestive heart failure. 904 38

The effects of increases in intracellular adenosine 3':5'-cyclic monophosphate (cyclic AMP) on bradykinin (BK)-induced generation of inositol phosphates (IPs) and Ca2+ mobilization were investigated in canine cultured tracheal smooth muscle cells (TSMCs). Pretreatment of TSMCs with either forskolin or dibutyryl cyclic AMP attenuated BK-stimulated responses. The inhibitory effects of these agents produced both a depression of the maximal response and a shift to the right of the concentration-response curves of BK. The water-soluble forskolin analogue L-858051, 7-deacetyl-7 beta-(r-N-methylpiperazino)-butyryl forskolin, significantly attenuated BK-stimulated IPs accumulation, while 1,9-dideoxy forskolin, an inactive forskolin, had little effect on IPs response. Moreover, SQ-22536, 9-(tetrahydro-2-furanyl)-9-H-purin-6-amine, an inhibitor of adenylate cyclase, and both H-89, N-(2-aminoethyl)-5-isoquinolinesulfonamide, and HA-1004, N-(2-guanidinoethyl)-5-isoquinolinesulfonamide, inhibitors of cyclic AMP-dependent protein kinase (PKA), reversed the ability of forskolin to attenuate BK-stimulated IPs accumulation. The KD and Bmax, values of the BK receptor for [3H]BK binding were not significantly changed by forskolin treatment for 30 min and 4 h. The AlF4(-)-induced IPs accumulation was attenuated by forskolin, indicating that G protein(s) are directly activated by AlF4- and uncoupled to phospholipase C by forskolin treatment. These results suggest that activation of cyclic AMP/PKA might inhibit the BK-stimulated PI breakdown and consequently reduce the [Ca2+]i increases or inhibit independently both responses, which is distal to the BK receptor in canine cultured TSMCs.
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PMID:Effect of forskolin on bradykinin-induced calcium mobilization in cultured canine tracheal smooth muscle cells. 911 15

Changes in contractile force were measured during isometric contraction of the bovine middle cerebral artery caused by stimulation of various receptors and by application of high K+, caffeine, and protein kinase C (PKC)-activators. The protein tyrosine kinase (PTK)-inhibitors, such as genistein and tyrphostin, were applied before testing the effect on the contractions or during the maximal plateau of the contraction. The contractions induced by serotonin, prostaglandin F2 alpha, endothelin-1, and thromboxane A2 were significantly and dose-dependently depressed by the PTK-inhibitors (IC50 2-15 microM). In contrast, contractions were significantly augmented by 1 microM pervanadate, an inhibitor of phosphoprotein tyrosine phosphatase. Lineweaver-Burk plotting of the dose-response curves with an increase in inhibitor concentration indicated that the receptor affinity for each agonist remained unchanged in spite of marked depression of the responses. Although the effect was not significant, contractions induced by both high K+ and caffeine were also depressed slightly by PTK-inhibitors in the same range of concentrations used for receptor-induced contractions. Contractions induced by PKC-activators, such as 1-oleoyl-2-acetyl-sn-glycerol and phorbol-12,13-diacetate, were significantly depressed by PTK-inhibitors at concentrations similar to those used for receptor-induced contractions. The results suggest that receptor stimulations which produce sequential activation of phospholipase C and PKC can activate PTK and trigger the so-called "PTK-cascade" causing a sustained or long-lasting contraction similar to the cerebral vasospasm observed clinically.
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PMID:Modulatory role of protein tyrosine kinase activation in the receptor-induced contractions of the bovine cerebral artery. 955 33

Activation of metabotropic glutamate receptors (mGluRs) with 1-aminocyclopentane-1S,3R-dicarboxylic acid 20 min prior to tetanus facilitates, or "primes," subsequent induction of long-term potentiation (LTP; Cohen and Abraham, J Neurophysiol 1996;76:953-962). In the present study, we investigated the receptor specificity and associated second messenger pathways involved in the mGluR priming effect by using field potentials recorded from area CA1 of rat hippocampal slices. In controls, mild theta-burst or high-frequency (100 Hz) stimulation induced 16% and 21% LTP, respectively. A 10-min application of the group I mGluR agonist 3,5-dihydroxyphenylglycine (DHPG) caused a transient depression of synaptic responses but a significant enhancement of subsequent LTP for both tetanus protocols (45% and 41% LTP, respectively). Maximal LTP, induced by stronger tetanization protocols, was not enhanced by DHPG, nor was mild LTP facilitated by post-tetanic application of DHPG. Priming with agonists selective for group II or III mGluRs had no effect on LTP. The mGluR antagonists L-2-amino-3-phosphonopropionic acid and 1-aminoindan-1,5-dicarboxylic acid inhibited the LTP facilitatory effect of DHPG but not the transient response depression, whereas alpha-methyl-4-carboxyphenylglycine produced the opposite effects. Priming with N-methyl-D-aspartate or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid did not facilitate LTP induction. Prior activation of muscarinic acetylcholine receptors produced at best a weak priming effect. Inhibition of phospholipase C by U-73122 completely abolished the priming of LTP by DHPG. We conclude that mGluR priming of LTP results from biochemical cascades triggered by activation of phospholipase C coupled to group I mGluRs.
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PMID:Priming of long-term potentiation induced by activation of metabotropic glutamate receptors coupled to phospholipase C. 957 22

Visual excitation in rhabdomeric photoreceptors is thought to be mediated by activation of a light-regulated phospholipase C (PLC) and the consequent hydrolysis of phosphatidylinositol bisphosphate. Whereas much attention has been devoted to inositol trisphosphate (IP3) production and intracellular Ca2+ release, little is known about the possible role of the DAG branch in the generation of the light response. We have tested the effect of chemically distinct surrogates of DAG on isolated Lima photoreceptors. Application of the phorbol ester PMA (0.5-10 microM) or the alkaloid (-)-indolactam (20-100 microM) from a holding potential of -50 mV elicited an inward current, several hundred picoamperes in amplitude, accompanied by a pronounced increase in membrane conductance. The stereoisomers 4alpha-PMA and (+)-indolactam were both inactive, arguing for the specificity of the effects. Elevation of cytosolic Ca2+ by intracellular dialysis accelerated this current, whereas chelerythrine antagonized it, suggesting the involvement of PKC. The reversal potential of the membrane current induced by PKC activators was approximately +10 mV; replacement of extracellular Na with impermeant N-methyl-D-glucamine decreased its amplitude and shifted the reversal potential in the negative direction. Stimulation by PMA and (-)-indolactam was accompanied by a pronounced depression of light responsiveness; conversely, steady illumination reduced the size of the current elicited by these PKC activators. Taken together, these results support the notion that the DAG branch of the PLC cascade, in addition to its suggested participation in visual adaptation, may play a role in the activation of the photoresponse or a component thereof, probably in synergy with IP3-mediated Ca2+ release.
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PMID:Membrane current induced by protein kinase C activators in rhabdomeric photoreceptors: implications for visual excitation. 965 Dec 8

1. During block of gamma-aminobutyric acid-A-mediated inhibition, low-frequency stimulation (2 Hz, 900 pulses) to Schaffer collateral-CA1 neuron synapses of adult rat hippocampus induced an N-methyl-D-aspartate receptor-independent, postsynaptic Ca2+-dependent depression of synaptic strength (long-term depression; LTD). 2. Ratio imaging with fura-2 revealed moderate dendritic [Ca2+] increases (approximately 500 nM) during only the initial approximately 30 s of the 7.5 min stimulation period. Conditioning for 30 s was, however, insufficient to induce LTD. 3. The [Ca2+] changes were insensitive to the metabotropic glutamate receptor (mGluR) antagonist (+)-alpha-methyl-4-carboxyphenylglycine (MCPG). MCPG, however, completely blocked LTD when present during conditioning. 4. The [Ca2+] changes were abolished by postsynaptic hyperpolarization (-110 mV at the soma). Hyperpolarizing neurons to -110 mV during conditioning significantly attenuated LTD induction. 5. LTD induction was also blocked by the postsynaptic presence of the protein kinase C inhibitor peptide PKC(19-36). 6. These results suggest that LTD induction in adult hippocampus by prolonged low-frequency stimulation depends on both a rapid Ca2+ influx through voltage-sensitive channels and synaptic stimulation of mGluRs which may be coupled to phospholipase C.
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PMID:Requirement of rapid Ca2+ entry and synaptic activation of metabotropic glutamate receptors for the induction of long-term depression in adult rat hippocampus. 971 58

The necessity for phospholipase C (PLC), the enzyme which produces the second messenger molecules inositol trisphosphate (IP3) and diacylglycerol, for the induction of long-term depression (LTD) was tested at Schaffer collateral-CA1 synapses in hippocampal slices in vitro. We report here that bath application of a selective cell-permeant PLC inhibitor, U-73122 (10 microM), does block the induction of LTD. In contrast, neither the inactive analog U-73343 (10 microM), nor application of U-73122 during the maintenance phase of LTD, impaired expression of LTD. Furthermore, postsynaptic infusion of U-73122 (100 microM) into single CA1 pyramidal neurons also prevented the induction of LTD. Since mGluR5 is the only metabotropic glutamate receptor subtype coupled to inositide turnover in field CA1, we conclude that the postsynaptic calcium store necessary for the induction of homosynaptic LTD is gated by IP3, through activation of mGluR5 coupled to phospholipase C.
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PMID:Postsynaptic phospholipase C activity is required for the induction of homosynaptic long-term depression in rat hippocampus. 973 84

1. We investigated the effect of adrenergic receptor stimulation or inhibition on the hepatic ultrastructural changes in a porcine faecal peritonitis model of multi-organ failure. We infused either the alpha1 adrenergic receptor agonist methoxamine or the beta2 adrenergic receptor antagonist ICI 118551 during 8 h of the study.2. Anaesthetized pigs (25-30 kg) were divided into four non-septic groups (control, non-septic, non-septic methoxamine and non-septic ICI 118551) and three septic groups (septic, septic methoxamine and septic ICI 118551).3. Changes in hepatic ultrastructure were measured by morphometric analysis. The septic group was significantly worse than all the non-septic groups. Septic methoxamine and septic ICI 118551 were significantly worse than the septic group.4. Septic methoxamine and septic ICI 118551 had a significantly increased perisinusoidal space; septic methoxamine had significant hepatocyte vacuolation.5. Hepatic ultrastructural changes were independent of hepatic blood flow.6. Septic methoxamine had significant myocardial depression.7. The alpha1 adrenergic receptor agonist methoxamine or the beta2 antagonist ICI 118551 both amplified the hepatic injury normally found during sepsis in our porcine model.8. These findings suggest that during sepsis a protective endogenous beta2 adrenergic receptor-mediated anti-inflammatory response is activated via cell membrane transduction to stimulate the trimeric G-protein complex Gs and activate the second cell messenger cAMP.9. In addition, it is likely that alpha1 adrenergic receptor agonists amplify the inflammatory response by stimulating the cell-surface receptor-linked trimeric G-protein complex to activate Gq and the second cell messenger phospholipase C.
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PMID:Porcine hepatic response to sepsis and its amplification by an adrenergic receptor alpha1 agonist and a beta2 antagonist. 974 23

1. The effects of increase in intracellular adenosine 3':5'-cyclic monophosphate (cAMP) on endothelin-1 (ET-1)-induced generation of inositol phosphates (IPs) and increase in intracellular Ca2+ ([Ca2+]i) were investigated in canine cultured tracheal smooth muscle cells (TSMCs). 2. Pretreatment of TSMCs with either cholera toxin (CTX; 10 microg ml(-1), 4 h), forskolin (10 microM, 30 min), or dibutyryl cAMP (1 mM, 30 min) inhibited ET-1-stimulated Ca2+ mobilization (by 23 +/- 5%, n = 8) and IPs accumulation (by 32 +/- 6%, n = 4). While after treatment with forskolin for 24 h, the cells retained the ability to respond to ET-1-induced Ca2+ mobilization to the same extent as the control group. 3. Forskolin (1-100 microM) inhibited the ET-1-induced increase in [Ca2+]i, but the lower concentrations had little effect on this response. The inhibitory effects of these agents produced both depression of the maximal response and a shift to the right of the concentration-response curve of ET-1 without changing the -logEC50 values. 4. The water-soluble forskolin analogue L-858051, 7-deacetyl-7beta-(gamma-N-methylpiperazino)-butyryl forskolin, significantly inhibited ET-1-stimulated IPs accumulation. In contrast, the addition of 1,9-dideoxy forskolin, an inactive analogue of forskolin, had little effect on stimulated responses. Moreover, SQ-22536, 9-(tetrahydro-2-furanyl)-9H-purin-6-amine, an inhibitor of adenylate cyclase, and both H-89, N-(2-aminoethyl)-5-isoquinolinesulfonamide, and HA-1004, N-(2-guanidinoethyl)-5-isoquinolinesulfonamide, inhibitors of cAMP-dependent protein kinase (PKA), attenuated the ability of forskolin to inhibit ET-1-induced IPs accumulation. These results suggest that activation of cAMP/PKA was involved in these inhibitory effects of forskolin. 5. The locus of this inhibition of forskolin treatment on AlF4(-)-stimulated IPs accumulation was investigated in canine TSMCs. The AlF4(-)-induced IPs accumulation was inhibited by forskolin, supporting that G protein(s) are directly activated by AlF4- and uncoupled to phospholipase C by forskolin treatment. 6. We conclude that cAMP elevating agents inhibit ET-1-stimulated generation of IPs and Ca2+ mobilization in canine cultured TSMCs. Since generation of IPs and increases in [Ca2+]i are very early events in the activation of ET-1 receptors, attenuation of these events by cAMP elevating agents might well contribute to the inhibitory effect of cAMP on tracheal smooth muscle function.
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PMID:Effect of forskolin on endothelin-induced phosphoinositide hydrolysis and calcium mobilization in cultured canine tracheal smooth muscle cells. 978 91

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