Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of increases in cellular adenosine 3'5'-cyclic monophosphate (cAMP) on 5-hydroxytryptamine-(5-HT-) induced generation of inositol phosphates (IPs) and increases in intracellular Ca2+ ([Ca2+]i) were investigated using canine cultured tracheal smooth muscle cells (TSMCs). Cholera toxin and forskolin induced concentration- and time-dependent cAMP formation with half-maximal effects (-logEC50) produced at concentrations of 7.0 +/- 0.5 and 4.9 +/- 0.4 respectively. Pretreatment of TSMCs with either forskolin or dibutyryl cAMP inhibited 5-HT-stimulated responses. Even after treatment for 24h, these agents still inhibited the 5-HT-induced Ca2+ mobilization. The inhibitory effects of these agents produced both depression of the maximal response and a shift to the right of the concentration response curves of 5-HT. The water-soluble forskolin analogue L-858051 [7-deacetyl-7beta-(gamma-N-methylpiperazino)-butyryl forskolin] significantly inhibited the 5-HT-stimulated accumulation of IPs. In contrast, the addition of 1,9-dideoxy forskolin, an inactive forskolin analogue, had little effect on this 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-isoquinolinesulphonamide] and HA-1004[N-(2-guanidinoethyl)-5-isoquinolinesulphonamide], inhibitors of cAMP-dependent protein kinase (PKA), attenuated the ability of forskolin to inhibit the 5-HT-stimulated accumulation of IPs. These results suggest that activation of cAMP/PKA was involved in these inhibitory effects of forskolin. The AlF4--induced accumulation of IPs was inhibited by forskolin, suggesting that G protein(s) are directly activated by AlF4-- and uncoupled from phospholipase C by forskolin treatment. These results suggest that activation of cAMP/PKA might inhibit the 5-HT-stimulated phosphoinositide breakdown and consequently reduce the [Ca2+]i increase or inhibit both responses independently.
...
PMID:Regulation of 5-hydroxytryptamine-induced calcium mobilization by cAMP-elevating agents in cultured canine tracheal smooth muscle cells. 876 73

Desensitization to serotonin (5-hydroxytryptamine, 5-HT)-facilitated dopamine release in vivo develops following either continuous or repeated pulses of 5-HT. For instance, an initial 20 min pulse of 5-HT (10 microM) produced a 715 +/- 150% increase in basal dopamine, an effect which steadily declined over 5 subsequent fractions to 222 +/- 80%. Also, secondary pulses (s2) of 5-HT administered 40 min following the primary pulse (s1), elicited a 327 +/- 16% increase in dopamine levels, significantly decreased from the primary s1 pulse. Augmentation of either protein kinase A or protein kinase C systems attenuated 5-HT-facilitated dopamine release, suggesting a role for protein kinases in regulating the desensitization process.
...
PMID:Desensitization of 5-hydroxytryptamine-facilitated dopamine release in vivo. 884 22

Achatin-I (Gly-D-Phe-Ala-Asp), a tetrapeptide having a D-phenylalanine residue and isolated from Achatina ganglia, has been proposed as an excitatory neurotransmitter of Achatina neurones. In the present study, it was demonstrated using Achatina giant neurones that achetin-I, perfused at alow concentration, enhanced an inward current (Iin) caused by 5-hydroxytryptamine (fast component) and an outward current (Iout) caused by FMRFamide (Phe-Met-Arg-Phe-NH2), and that this peptide suppressed an Iin caused by oxytocin, and Iout caused by acetylcholine and APGW-amide (Ala-Pro-Gly-Trp-NH2). These findings indicate that achatin-I acts not only as a neurotransmitter but also as a neuromodulator for these neurones. In the preliminary experiments, it was shown that an Iin caused by achatin-I on an Achatina giant neurone type, PON (periodically oscillating neurone), was suppressed by H-89 (a PKA inhibitor) and W-7 (calmodulin inhibitor), and that an Iin caused by achatin-I on v-RCON (ventral-right cerebral distinct neurone) was suppressed by KT5823 (PKG inhibitor), suggesting that achatin-I acts on PON via the cyclic AMP-PKA system and on v-RCON via the cyclic GMP-PKG system. Moreover, calmodulin would play a role to produce the Iin for achatin-I on PON via the system mentioned.
...
PMID:Further study on the effects of achatin-I, an Achatina endogenous neuroexcitatory tetrapeptide having a D-phenylalanine residue, on Achatina neurones. 885 10

The depolarization of adult and neonatal rat facial and spinal motoneurones by 5-hydroxytryptamine (5-HT) in part involves an enhancement of the hyperpolarization-activated, inward-rectifier, IH. Under experimental conditions which promote this action, 5-HT evokes an inward current which can be mimicked by intracellularly applied adenosine 3',5'-cyclic monophosphate (cAMP) and potentiated by the cAMP-specific phosphodiesterase inhibitor Ro 20-1724. In this study, we show that this action of 5-HT can be blocked by the adenylyl cyclase inhibitors 2'3'-dideoxyadenosine (2',3'-DDA). 5'-adenylimidodiphosphate (AMP-PNP) and SQ-22536 (9-(tetrahydro-2-furyl)adenine), but not by external or internal application of the protein kinase inhibitors H-7, staurosporine and chelerythrine. The most recently cloned 5-HT receptor subtypes, 5-HT4, 5-HT6 and 5-HT7, can all stimulate adenylyl cyclase when activated. In the presence of internal GTP-gamma-S, 5-HT irreversibly enhanced IH. The 5-HT-induced inward current could be reversibly blocked by methysergide, but not by the 5-HT4 receptor antagonist GR-113808A, the 5-HT6 and 5-HT7 antagonist clozapine and the 5-HT1A antagonist WAY-100365. 5-Methoxytryptamine (5-MeOT) and 5-carboxamidotryptamine (5-CT) mimicked the action of 5-HT with a rank order of potency of 5-HT = 5MeOT > 5-CT. Surprisingly, 8-hydroxy-2-(di-N-propylamino)-tetralin (8-OH DPAT), a 5-HT1A and 5-HT7 agonist was inactive on facial motoneurones unlike its reported agonist action on spinal motoneurones. It is proposed that cAMP produced by 5-HT-mediated stimulation of adenylyl cyclase acts in a phosphorylation-independent manner, possibly directly, on the IH channel. The 5-HT receptor subtype mediating this response cannot be correlated with any of the classified 5-HT receptor subtypes that stimulate adenylyl cyclase.
...
PMID:Modulation of IH by 5-HT in neonatal rat motoneurones in vitro: mediation through a phosphorylation independent action of cAMP. 922 99

Antidepressant-sensitive serotonin (5-hydroxytryptamine, 5HT) transporters (SERTs) are responsible for efficient synaptic clearance of extracellular 5HT. Previously (Qian, Y., Galli, A., Ramamoorthy, S., Risso, S., DeFelice, L. J., and Blakely, R. D. (1997) J. Neurosci. 17, 45-47), we demonstrated that protein kinase (PKC)-linked pathways in transfected HEK-293 cells lead to the internalization of cell-surface human (h) SERT protein and a reduction in 5HT uptake capacity. In the present study, we report that PKC activators rapidly, and in a concentration-dependent manner, elevate the basal level of hSERT phosphorylation 5-6-fold. Similarly, protein phosphatase (PP1/PP2A) inhibitors down-regulate 5HT transport and significantly elevate hSERT 32P incorporation, effects that are additive with those of PKC activators. Moreover, hSERT phosphorylation induced by beta-phorbol 12-myristate 13-acetate is abolished selectively by the PKC inhibitors staurosporine and bisindolylmaleimide I, whereas hSERT phosphorylation induced by phosphatase inhibitors is insensitive to these agents at comparable concentrations. Protein kinase A and protein kinase G activators fail to acutely down-regulate 5HT uptake but significantly enhance hSERT phosphorylation. Basal hSERT and okadaic acid-induced phosphorylation were insensitive to chelation of intracellular calcium and Ca2+/calmodulin-dependent protein kinase inhibitors. Together these results reveal hSERT to be a phosphoprotein whose phosphorylation state is likely to be tightly controlled by multiple kinase and phosphatase pathways that may also influence the transporter's regulated trafficking.
...
PMID:Phosphorylation and regulation of antidepressant-sensitive serotonin transporters. 944 97

1. Extracellular adenosine triphosphate (ATP) is mitogenic for vascular smooth muscle cells (VSMC) and stimulates several events that are important for cell proliferation: DNA synthesis, protein synthesis, increase of cell number, immediate early genes, cell-cycle progression, and tyrosine phosphorylation. 2. Receptor characterization indicates mitogenic effects of both P2U and P2Y receptors. The P2X receptor is lost in cultured VSMC and is not involved. Several related biological substances such as UTP, ITP, GTP, AP4A, ADP, and UDP are also mitogenic. 3. Signal transduction is mediated via Gq-proteins, phospholipase C beta, phospholipase D, diacyl glycerol, protein kinase C alpha, delta, Raf-1, MEK, and MAPK. 4. ATP acts synergistically with polypeptide growth factors (PDGF, bFGF, IGF-1, EGF, insulin) and growth factors acting via G-protein-coupled receptors (noradrenaline, neuropeptide Y, 5-hydroxytryptamine, angiotensin II, endothelin-1). 5. The mitogenic effects have been demonstrated in rat, porcine, and bovine VSMC and cells from human coronary arteries, aorta, and subcutaneous arteries and veins. 6. The trophic effects on VSMC and the abundant sources for extracellular ATP in the vessel wall make a pathophysiological role probable in the development of atherosclerosis, neointima-formation after angioplasty, and possibly hypertension.
...
PMID:Extracellular ATP: a growth factor for vascular smooth muscle cells. 959 70

The actions of serotonin on rat basolateral amygdala neurons were studied with conventional intracellular recording techniques and fura-2 fluorimetric recordings. Bath application of 5-hydroxytryptamine (5-HT or serotonin) reversibly suppressed the excitatory postsynaptic potential in a concentration-dependent manner without affecting the resting membrane potential and neuronal input resistance. Extracellular Ba2+ or pertussis toxin pretreatment did not affect the depressing effect of 5-HT suggesting that it is not mediated through activation of Gi/o protein-coupled K+ conductance. The sensitivity of postsynaptic neurons to glutamate receptor agonist was unaltered by the 5-HT pretreatment. In addition, the magnitude of paired-pulse facilitation was increased in the presence of 5-HT indicating a presynaptic mode of action. The effect of 5-HT was mimicked by the selective 5-HT1A agonist 8-hydroxy-dipropylaminotetralin (8-OH-DPAT) and was blocked by the selective 5-HT1A antagonist 1-(2-methoxyphenyl)-4[4-(2-phthalimido)butyl]piperazine oxadiazol-3-yl]methyl]phenyl]-methanesulphonamide. In contrast, the selective 5-HT2 receptor antagonist ketanserin failed to affect the action of 5-HT. The effects of 5-HT and 8-OH-DPAT on the high K+-induced increase in [Ca2+]i were studied in acutely dissociated basolateral amygdala neurons. High K+-induced increase in [Ca2+]i was blocked by Ca2+-free solution and Cd2+ suggesting that Ca2+ entry responsible for the depolarization-evoked increase in [Ca2+]i occurred through voltage-dependent Ca2+ channels. Application of 5-HT and 8-OH-DPAT reduced the K+-induced Ca2+ influx in a concentration-dependent manner. The effect of 5-HT was completely abolished in slices pretreated with Rp-cyclic adenosine 3',5'-monophosphothioate (Rp-cAMP), a regulatory site antagonist of protein kinase A, suggesting that 5-HT may act through a cAMP-dependent mechanism. Taken together, these results suggest that functional 5-HT1A receptors are present in the excitatory terminals and mediate the 5-HT inhibition of synaptic transmission in the amygdala.
...
PMID:Serotonin depresses excitatory synaptic transmission and depolarization-evoked Ca2+ influx in rat basolateral amygdala via 5-HT1A receptors. 975 2

The effect of forskolin on 5-hydroxytryptamine (5-HT)-induced inositol phosphate (IP) and Ca2+ mobilisation was investigated in canine cultured aorta smooth muscle cells (ASMCs). Pretreatment of ASMCs with forskolin attenuated 5-HT-induced IP accumulation and Ca2+ mobilisation in a time- and concentration-dependent manner. The half-maximal effects (pEC50) of forskolin to attenuate IP and Ca2+ responses to 5-HT occurred at concentrations of 6.28 and 6.64, respectively. Pretreatment of ASMCs with cholera toxin caused a similar inhibition on 5-HT-induced responses. Even after treatment with forskolin for 24 h, the 5-HT-induced responses were still inhibited. The inhibitory effect of forskolin resulted from both a depression of the maximal response and a shift to the right of the concentration-effect curves of 5-HT in these responses. The water-soluble forskolin analogue L-858051 [7-deacetyl-7beta-(gamma-N-methylpiperazino)-butyryl forskolin] significantly inhibited the 5-HT-stimulated IP accumulation. In contrast, the addition of 1,9-dideoxy forskolin, an inactive forskolin analogue, had little effect on IP 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-iosquinolinesulphonamide] and HA-1004 [N-(2-guanidinoethyl)-5-iosquinolinesulphonamide], inhibitors of cAMP-dependent protein kinase (PKA), attenuated the ability of forskolin to inhibit the 5-HT-stimulated accumulation of IP in ASMCs. These results indicate that activation of cAMP/PKA might inhibit the 5-HT-stimulated IP accumulation and consequently reduce Ca2+ mobilisation, or inhibit both responses independently.
...
PMID:Forskolin inhibits 5-hydroxytryptamine-induced phosphoinositide hydrolysis and Ca+2 Mobilisation in canine cultured aorta smooth muscle cells. 1053 Aug 79

In renal mesangial cells, activation of protein tyrosine kinase receptors may increase the activity of mitogen-activated protein (MAP) kinases and subsequently induce expression of prostaglandin G/H synthase-2 (PGHS-2, cyclo-oxygenase-2). As examples, platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) were shown to transiently enhance p42/44 MAP kinase activity, which was an essential step in the induction of PGHS-2 mRNA and protein. Inhibitors of receptor kinase activities, tyrphostins AG1296 and AG1478, specifically inhibited the effects of PDGF and EGF respectively. Activation of p42/44 and p38 MAP kinases and PGHS-2 induction were also mediated by lysophosphatidic acid (LPA), which binds to pertussis-toxin-sensitive G-protein-coupled receptors. LPA stimulation was inhibited by AG1296, but not AG1478, indicating involvement of the PDGF receptor kinase in LPA-mediated signalling. This was confirmed by pertussis-toxin-sensitive tyrosine phosphorylation of the PDGF receptor by LPA, whereas no phosphorylation of the EGF receptor was detected. For comparison, 5-hydroxytryptamine ('serotonin')-mediated signalling was only partially inhibited by AG1296, and also not affected by AG1478. A strong basal AG1296-sensitive tyrosine phosphorylation of the PDGF receptor and a set of other proteins was observed, which by itself was not sufficient to induce p42/44 MAP kinase activation, but played an essential role not only in LPA- but also in phorbol ester-mediated activation. Taken together, the PDGF receptor, but not the EGF receptor, is involved in LPA-mediated MAP kinase activation and PGHS-2 induction in primary mesangial cells, where both protein kinase receptors are present and functionally active.
...
PMID:The platelet-derived-growth-factor receptor, not the epidermal-growth-factor receptor, is used by lysophosphatidic acid to activate p42/44 mitogen-activated protein kinase and to induce prostaglandin G/H synthase-2 in mesangial cells. 1062 Apr 97

Major adaptations after chronic exposure to morphine include an up-regulation of the adenosine 3',5'-monophosphate pathway. Acute opioids, via mu-opioid receptors, disinhibit midbrain serotonergic neurons by suppressing inhibitory GABAergic transmission in the dorsal raphe nucleus and adjacent periaqueductal gray. This study examined whether chronic morphine induces a compensatory increase in GABA inputs to 5-hydroxytryptamine neurons and whether this was associated with an up-regulation of the adenosine 3',5'-monophosphate pathway. The firing rate of serotonergic neurons was reduced in brain slices from morphine-dependent rats, an effect reversed by the GABA(A) antagonist bicuculline. The reduction in firing rate was accompanied by an increased frequency of spontaneous GABAergic inhibitory postsynaptic currents, indicating increased GABA tone in the slice. The increase in GABA tone in brain slices from dependent rats was associated with increased induction of inhibitory postsynaptic currents by the adenylyl cyclase activator forskolin, suggesting an up-regulation of the adenosine 3',5'-monophosphate pathway. Indeed, chronic morphine increased levels of adenylyl cyclase VIII (but not of adenylyl cyclase I, III or V) immunoreactivity in the dorsal raphe nucleus area. Two adenosine 3',5'-monophosphate-mediated mechanisms for the increase in GABA tone were discerned. The first, which predominated when impulse-flow was blocked by tetrodotoxin, involves protein kinase A since it was sensitive to protein kinase A inhibitors. The second, seen when impulse-flow was intact (i.e. absence of tetrodotoxin), was insensitive to protein kinase A inhibitors but was suppressed by ZD7288, a blocker of hyperpolarizing-activated Ih channels which are directly activated by adenosine 3',5'-monophosphate. We conclude that chronic morphine induces an up-regulation of the adenosine 3',5'-monophosphate pathway in GABAergic inputs to serotonergic cells, resulting in an increase in spontaneous and impulse-flow dependent GABA release. These changes would lead to an increase in GABA tone and subsequently to the reported decrease in serotonergic activity during opiate withdrawal.
...
PMID:Chronic morphine increases GABA tone on serotonergic neurons of the dorsal raphe nucleus: association with an up-regulation of the cyclic AMP pathway. 1065 23


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---