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)

1. A characteristic feature of vasoconstrictor 5-HT1-like receptors in vitro is that responses mediated by these receptors are enhanced by other vasoconstrictor agents. In the present study, we have examined the influence of cellular cyclic AMP on vasoconstrictor responses to activation of 5-HT1-like receptors in isolated ring segments of the rabbit femoral artery (RbFA), and determined whether modulation of this second messenger underlies the ability of angiotensin II, an endogenous vasoconstrictor, to enhance 5-HT1-like responses. 2. In the presence of 0.1 microM ketanserin (to antagonize 5-HT2-receptors) and 0.3 microM prazosin (to antagonize alpha 1-adrenoceptors), 5-HT produced a concentration-related contraction, which was significantly augmented by pre-contraction of the vessel with 0.1-0.45 nM ([A30]) angiotensin II. Responses to 5-HT in the presence of angiotensin II were inhibited by the 5-HT1-like/5-HT2 antagonist, metergoline (1 microM). 3. The directly-acting adenylyl cyclase activator, forskolin (1 microM), abolished responses to angiotensin II and caused a rightward shift and concomitant depression of the 5-HT concentration-effect (E/[A]) curve. Higher concentrations of forskolin (> 10 microM) abolished responses to 5-HT and 1 microM sodium nitroprusside abolished responses to 5-HT and angiotensin II (n = 7). 4. In the presence of angiotensin II (0.1-0.45 nM), however, 1 microM forskolin failed to inhibit 5-HT-induced contractions; the E/A curve for 5-HT (in the presence of forskolin and angiotensin II) was not significantly different from that produced in the presence of angiotensin II alone. Similarly, the presence of angiotensin II (0.1-0.45 nM) was also able to overcome partially the inhibitory effect of 1 microM sodium nitroprusside against 5-HT-induced contractions (n = 7). In marked contrast, 5-HT failed to elicit a contraction in the presence of angiotensin II and 10 microM forskolin (n = 5). 5. 5-HT (1 microM) significantly reduced basal cyclic AMP accumulation by 35%, whereas angiotensin II (0.45 nM) was without effect. The combination of angiotensin II and 5-HT failed to alter significantly the reduction in cyclic AMP produced by 5-HT alone. Forskolin (1 microM) increased cyclic AMP levels 7 fold above basal, but neither 1 microM 5-HT nor a combination of 1 microM 5-HT and 0.45 nM angiotensin II produced a significant decrease in cyclic AMP content. 6. Whilst moderate concentrations of forskolin can inhibit the responses to either agent, simultaneous activation of angiotensin II and 5-HT1-like receptors can overcome the inhibitory effect of elevated levels of cyclic AMP. Since the potentiating effect of angiotensin II, in either the presence or absence of forskolin, occurs without significant alteration of cellular cyclic AMP, it seems likely that a cyclic AMP-independent pathway is implicated in the synergistic interaction between angiotensin II and vasoconstrictor 5-HT1-like receptors.
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PMID:The effect of forskolin on 5-HT1-like and angiotensin II-induced vasoconstriction and cyclic AMP content of the rabbit isolated femoral artery. 876 87

The effects of tetrahydro-9-aminoacridine (THA) on beta-adrenoceptor activation-induced synaptic potentiation were studied in brain slices of the rat amygdala using intracellular recording techniques. To exclude the involvement of N-methyl-D-aspartate (NMDA) receptors, all the experiments were performed in the presence of NMDA receptor antagonist, D-APV (50 microM). Bath application of isoproterenol (Iso; 15 microM) results in a long-lasting enhancement of the amplitude of excitatory postsynaptic potentials (EPSPs) to 200 +/- 6% of baseline. Forskolin, which directly activates adenyl cyclase, produces a similar effect suggesting that Iso may act through a cyclic AMP-dependent mechanism. Pretreatment of the slices with THA (300 microM) completely abolishes the Iso- and forskolin-induced synaptic potentiation. We hypothesize that the locus of THA/beta-adrenoceptor interaction is presynaptic; the underlying mechanism is likely due to THA's depression of transmitter release via a presynaptic blockade of voltage-dependent Ca2+ channels.
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PMID:Blockade of isoproterenol-induced synaptic potentiation by tetra-9-aminoacridine in the rat amygdala. 887 90

The effect of baclofen on the function of the gamma-aminobutyric acidA (GABAA) receptor was examined in acutely dissociated neurons of bullfrog dorsal root ganaglia (DRG) by using the whole-cell voltage-clamp method. Baclofen (0.1-100 microM) depressed the inward currents produced by GABA (100 microM) and muscimol (100 microM). Baclofen shifted the concentration-response curve for GABA (1 microM-1 mM) downward. Baclofen decreased the maximum response (Vmax) to GABA without changing the apparent dissociation constant (Kd), suggesting a noncompetitive antagonism. The effect of baclofen on the GABA current was blocked by antagonists for the GABAB receptor; the rank order of potency was P-[3-Aminopropyl]-P-diethoxymethylphosphinic acid (CGP 55845A) > > 3-N[1-(S)-(3,4-dichlorophenyl)ethyl]amino-2-(S)-hydroxypropyl-P- benzyl-phosphinic acid (CGP 35348) > saclofen > > phaclofen. Baclofen produced an irreversible depression of the GABA current in neurons dialyzed with an internal solution containing guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S, 100 microM). Intracellular guanosine 5'-O-(2-thiodiphosphate) (GDP beta S, 100 microM) blocked the inhibitory effect of baclofen on the GABA current. Forskolin (10 microM) and dibutyryl N6, 2'-O-dibutyryladenosine 3':5'-cyclic monophophate (db-cyclic AMP) (200 microM) depressed the GABA current. N-(2-aminoethyl)-5-isoquinolinesulfonamide (H-9, 40 microM) and N-(2-guanidinoethyl)-5-isoquinolinesulfonamide (HA-1004, 50 microM), protein kinase A (PKA) inhibitors, reduced the depressant effect of baclofen on the GABA current. The baclofen-induced depression of the GABA current was blocked by PKI(5-24), a specific PKA inhibitor, but not by PKC(19-36), a specific protein kinase C (PKC) inhibitor. We suggest that GABAB receptors regulate the GABAA receptor function through a G-protein linked to the adenylyl cyclase-PKA pathway in bullfrog DRG neurons.
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PMID:Baclofen reduces GABAA receptor responses in acutely dissociated neurons of bullfrog dorsal root ganglia. 913 75

We investigated platelet adenylyl cyclase activity in 17 subjects with a history of major depression ("depressed subjects") and 20 controls. Forskolin was used to directly activate adenylyl cyclase, while guanine nucleotides (Gpp(NH)p) and fluoride ions were used to measure adenylyl cyclase activity modulated through the G proteins. Forskolin-stimulated adenylyl cyclase was significantly lower in the depressed subjects (p < 0.0005). There was a statistically significant difference in basal adenylyl cyclase activity between male depressed subjects and male controls. The basal adenylyl cyclase activity was also lower in female depressed subjects, but this difference did not reach statistical significance (p < 0.2). The adenylyl cyclase activity measured after stimulation with a guanine nucleotide or cesium fluoride did not differ between control and depressed male or female subjects. Severity of current depression and the current use of antidepressant medication were not related to the lower forskolin-stimulated enzyme activity in the depressed subjects. The difference in forskolin-stimulated adenylyl cyclase activity appears to reflect a qualitative difference in the adenylyl cyclase enzyme activity in persons with a history of major depression.
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PMID:Forskolin-stimulated platelet adenylyl cyclase activity is lower in persons with major depression. 919 39

Previous studies have demonstrated blunted beta-adrenergic responsivity in leukocytes from depressed patients. We sought to determine if this blunted cyclic adenosine monophosphate (AMP) response is specific for beta-adrenergic receptors (homologous), or whether other adenylyl cyclase-coupled receptors are also involved (heterologous), in order to localize this effect at the level of the receptor versus the coupling protein or the transducer, adenylyl cyclase. We studied adenylyl cyclase-mediated responses in peripheral blood mononuclear cells from 95 drug-free patients with a major depressive episode and 69 healthy controls. We found a similar degree of decrease in the peak cyclic AMP response to activation of the beta-adrenergic receptor (28%) and the prostaglandin receptor (34%) in the depressed patients, which indicated heterologous desensitization. Forskolin cyclic AMP responses were not blunted. Blunting of cyclic AMP responses to isoproterenol did not appear to correlate with levels of plasma norepinephrine and epinephrine or hypothalamic-pituitary-adrenocortical function. The absence of a decrease in the peak forskolin-generated cyclic AMP response, which involves direct activation of adenylyl cyclase, suggests an abnormality at the level of the coupling protein in these adenylyl-coupled receptors in depressed patients. Future studies need to determine whether this leukocyte signal transduction defect in depression also involves brain adenylyl cyclase-coupled receptors.
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PMID:Subsensitivity of adenylyl cyclase-coupled receptors on mononuclear leukocytes from drug-free inpatients with a major depressive episode. 935 70

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

Beta-adrenergic agonists (beta-AA) enhance protein accretion in skeletal muscles. This stimulation is characterized by increased protein synthesis, increased expression of myofibrillar protein genes and a depression in protein degradation in animals, and increased proliferation and DNA synthesis in muscle cells in vitro. The mechanism or signal path in muscle whereby beta-AA would elicit these physiological effects upon binding to the G protein-coupled beta-adrenergic receptor (beta-AR) is unclear. C2C12 myoblasts were used to determine beta-AR ligand binding characteristics, cyclic AMP synthesis in response to isoproterenol (ISO) stimulation, and effects of ISO on DNA synthesis, mitogen activated protein kinase (MAPK), and fibronectin (FN) gene expression. Results showed that C2C12 cells possess beta-AR which are specific, saturable, and of high affinity (Kd = 0.2 nM). Forskolin and ISO stimulated cAMP production by = 20-fold (P<0.001) and 17-fold (P<0.001), respectively. ISO and the cAMP analog, 8-bromo-cAMP (8-BC) stimulated DNA synthesis in proliferating cells by 150% (P<0.05) and 200% (P<0.01), respectively, without modulating MAPK activity, whereas addition of fetal bovine serum to culture resulted in a 500% increase (P<0.01) in DNA synthesis and MAPK activation. DNA synthesis in C2C12 cells treated with ISO, 8-BC, or FBS was abolished in the presence of 25 microM PD098059, an MAPK-kinase inhibitor, suggesting that an MAPK-dependent pathway is likely involved in C2C12 proliferation. During cAMP elevating agent stimulation, basal MAPK activity may be sufficient, in the presence of other putative signaling molecules, to support proliferation in these cells. ISO or 8-BC treatment increased FN mRNA by three- and seven-fold, respectively, in growing C2C12 cells implying a connection between increased DNA synthesis and FN gene expression.
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PMID:Beta-adrenergic agonist hyperplastic effect is associated with increased fibronectin gene expression and not mitogen-activated protein kinase modulation in C2C12 cells. 1071 44

In the present study, possible mechanisms involved in the tetanus-induced potentiation of gamma-aminobutyric acid-A (GABA-A) receptor-mediated inhibitory postsynaptic currents (IPSCs) were investigated using the whole cell voltage-clamp technique on CA1 neurons in rat hippocampal slices. Stimulations (100 Hz) of the stratum radiatum, while voltage-clamping the membrane potential of neurons, induces a long-term potentiation (LTP) of evoked fast IPSCs while increasing the number but not the amplitude of spontaneous IPSCs (sIPSCs). The potentiation of fast IPSCs was input specific. During the period of IPSC potentiation, postsynaptic responses produced by 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol hydrochloride and baclofen, GABA-A and GABA-B agonists respectively, were not significantly different from control. CGP 36742, a GABA-B antagonist, blocked the induction of tetanus-induced potentiation of evoked and spontaneous IPSCs, while GTPgammaS, an activator of G proteins, substitution for GTP in the postsynaptic recording electrode did not occlude potentiation. Since GABA-B receptors work through G proteins, our results suggest that pre- but not postsynaptic GABA-B receptors are involved in the potentiation of fast IPSCs. A tetanus delivered when GABA-A responses were completely blocked by bicuculline suggests that GABA-A receptor activation during tetanus is not essential for the induction of potentiation. Rp-cAMPs, an antagonist of protein kinase A (PKA) activation, blocks the induction of potentiation of fast IPSCs. Forskolin, an activator of PKA, increases baseline evoked IPSCs as well as the number of sIPSCs, and a tetanic stimulation during this enhancement uncovers a long-term depression of the evoked IPSC. Sulfhydryl alkylating agents, N-ethylmaleimide and p-chloromercuribenzoic acid, which have been found to presynaptically increase GABA release and have been suggested to have effects on proteins involved in transmitter release processes occurring in nerve terminals, occlude tetanus-induced potentiation of evoked and spontaneous IPSCs. Taken together our results suggest that LTP of IPSCs originates from a presynaptic site and that GABA-B receptor activation, cyclic AMP/PKA activation and sulfhydryl-alkylation are involved. Plasticity of IPSCs as observed in this study would have significant implications for network behavior in the hippocampus.
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PMID:Mechanisms involved in tetanus-induced potentiation of fast IPSCs in rat hippocampal CA1 neurons. 1084 57

The present study examined the activities of adenylyl cyclase (AC) and rolipram-sensitive phosphodiesterase (PDE4) on brain regions in learned helplessness rat in order to clarify the cyclic AMP (cAMP) regulation system in the depressive state. Rats exposed to inescapable footshocks once a day for 3 days exhibited a significant increase in escape failure on Day 1 (the day after the last inescapable shock day) and Day 7. The plasma corticosterone level in rats subjected to inescapable shocks was significantly higher than that of nonstressed control rats on Days 1 and 7. The PDE4 activity of the frontal cortex was significantly lower than that of nonstressed control rats on Day 1. However, on Day 7, the PDE4 and [3H]-rolipram binding activities were significantly increased in the frontal cortex and hippocampus of learned helplessness rats compared with those of nonstressed control rats. Forskolin-stimulated AC activity was significantly decreased in the frontal cortex, hippocampus and striatum of learned helplessness rats on Day 1, but not on Day 7. Thus, a decrease in both AC and PDE4 activities was noted in the acute depressive state. In contrast, increase of PDE4 activity was noted in the delayed depressive phase, although no change of AC activity was observed. Gel shift assays also showed the decrease of cAMP-response element (CRE)-binding activity relating to cAMP activity in the frontal cortex and hippocampus of learned helplessness rats on Days 1 and 7. These findings indicated a delayed increase in PDE4 activity leading to hypofunction of the cAMP-dependent signal transduction system in the frontal cortex and hippocampus of learned helplessness rats, suggesting that up-regulation of the cAMP-degradation system by PDE4 may play a pivotal role in pathological states of chronic depression.
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PMID:Different regulation of adenylyl cyclase and rolipram-sensitive phosphodiesterase activity on the frontal cortex and hippocampus in learned helplessness rats. 1457 86

Prostanoids can suppress vascular smooth muscle cell (VSMC) proliferation, but the mechanism through which this is mediated has not been identified. In this study, we show rat aortic VSMCs to express the EP1, EP2, EP3, EP4, and IP receptors. The EP4 receptor-specific agonist, 11-deoxy-PGE1, induced a time-dependent phosphorylation of protein kinase C and extracellular signal-regulated kinase (ERK) 1/2 in serum-depleted (0.1%) VSMCs, whereas the EP2 receptor agonist, butaprost, was without effect. PGI2 or iloprost at the IP receptor inhibited basal ERK phosphorylation with IC50 values of 10 nmol/L. Iloprost also attenuated the sustained activation of ERK induced by endothelin-1 or basic fibroblast growth factor (bFGF). Endothelin-1 or bFGF significantly increased the number of VSMCs counted 24 hours later compared with basal, and both responses were blocked by the MEK inhibitor, U0126, or iloprost. Under basal conditions, U0126 or iloprost reduced the number of viable cells and increased caspase-3 activity, which could be reversed by coapplication with endothelin-1, bFGF, or the adenylate cyclase inhibitor, SQ22536. Endothelin-1, bFGF, or SQ22536 prevented the depression to below basal levels of ERK phosphorylation induced by iloprost. Forskolin activated caspase-3 and attenuated basal ERK phosphorylation, which were prevented by SQ22536, endothelin-1, or bFGF. These data suggest that iloprost induces apoptosis via a cAMP-mediated suppression of ERK activity. In turn, this apoptotic response can be blocked by a mitogenic stimulus that re-establishes ERK activity back to basal levels, but at the expense of any concomitant proliferative activity. However, ERK stimulation by a selective EP4 receptor agonist, suggests that prostanoids may have diverse and complex roles in VSMC physiology.
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PMID:Prostacyclin induces apoptosis of vascular smooth muscle cells by a cAMP-mediated inhibition of extracellular signal-regulated kinase activity and can counteract the mitogenic activity of endothelin-1 or basic fibroblast growth factor. 1496 6


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