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

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

Effects of 5-hydroxytryptamine (5-HT) on inhibitory synaptic transmission in the rat dorsolateral septal nucleus (DLSN) were examined by conventional intracellular and voltage-clamp recording methods. 5-HT (1-30 microM) depressed the monosynaptic fast IPSC evoked by local stimulation of the DLSN in the presence of DNQX, AP5 and CGP 55845A. CP 93129, a selective 5-HT1B receptor agonist, depressed the fast IPSC. The 5-HT-induced depression of the fast IPSC was attenuated by SB 216641, a selective antagonist for 5-HT1B receptors. 5-HT did not change the inward currents mediated by GABAA receptors, suggesting that 5-HT presynaptically inhibited the fast IPSC. 5-HT and CP 93129 depressed the frequency of miniature fast IPSPs (mIPSPs) without changing their amplitudes. Neither a selective protein kinase A inhibitor, H-89, nor a selective protein kinase C inhibitor, calphostin C, blocked the 5-HT-induced depression of the fast IPSC. N-Ethylmaleimide (NEM) blocked the 5-HT-induced depression of the evoked IPSC. These results suggest that activation of presynaptic 5-HT1B receptors depresses the release of GABA via a pertussis toxin (PTX)-sensitive G-protein in the rat DLSN.
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PMID:5-Hydroxytryptamine 1B receptors mediate presynaptic inhibition of monosynaptic IPSC in the rat dorsolateral septal nucleus. 1515 69

Serotonin (5-hydroxytryptamine; 5-HT) transporters (SERTs) are critical determinants of synaptic 5-HT inactivation and the targets for multiple drugs used to treat psychiatric disorders. In support of prior studies, we found that short-term (5-30 min) application of the adenosine receptor (AR) agonist 5'-N-ethylcarboxamidoadenosine (NECA) induces an increase in 5-HT uptake Vmax in rat basophilic leukemia 2H3 cells that is enhanced by pretreatment with the cGMP phosphodiesterase inhibitor sildenafil. NECA stimulation is blocked by the A3 AR antagonist 3-ethyl-5-benzyl-2-methyl-phenylethynyl-6-phenyl-1,4(+/-)dihydropyridine-3,5-dicarboxylate (MRS1191), by the phospholipase C inhibitor 1-(6-[[17beta-3-methoxyestra-1,3,5(10)-trien-17-yl] amino]hexyl)-1H-pyrrole-2,5-dione (U73122), by the intracellular Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester, and by the guanyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. Hydroxylamine, a nitric-oxide donor, and 8-bromo-cGMP, a membrane-permeant analog of cGMP, mimic the effects of NECA on 5-HT uptake, whereas the protein kinase G (PKG) inhibitor N-[2-(methylamino)ethy]-5-isoquinoline-sulfonamide (H8) blocks NECA, hydroxylamine, and 8-bromo-cGMP effects. NECA stimulation activates p38 mitogen-activated protein kinase (MAPK), whereas p38 MAPK inhibitors block NECA stimulation of SERT activity, as does the protein phosphatase 2A (PP2A) inhibitor calyculin A. 5-HT-displaceable [125I]3beta-(4-iodophenyl)-tropane-2beta-carboxylic acid methylester tartrate (RTI-55) whole-cell binding is increased by NECA or sildenafil, and both surface binding and cell surface SERT protein are elevated after NECA or sildenafil stimulation of AR/SERT-cotransfected Chinese hamster ovary cells. Whereas p38 MAPK inhibition blocks NECA stimulation of 5-HT activity, it fails to blunt stimulation of SERT surface density. Moreover, inactivation of existing surface SERTs fails to eliminate NECA stimulation of SERT. Together, these results reveal two PKG-dependent pathways supporting rapid SERT regulation by A3 ARs, one leading to enhanced SERT surface trafficking, and a separate, p38 MAPK-dependent process augmenting SERT intrinsic activity.
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PMID:Adenosine receptor, protein kinase G, and p38 mitogen-activated protein kinase-dependent up-regulation of serotonin transporters involves both transporter trafficking and activation. 1515 39

Serotonin (5-hydroxytryptamine, 5-HT) increases contractile force and elicits arrhythmias through 5-HT(4) receptors in porcine and human atrium, but its ventricular effects are unknown. We now report functional 5-HT(4) receptors in porcine and human ventricle. 5-HT(4) mRNA levels were determined in porcine and human ventricles and contractility studied in ventricular trabeculae. Cyclic AMP-dependent protein kinase (PKA) activity was measured in porcine ventricle. Porcine and human ventricles expressed 5-HT(4) receptor mRNA. Ventricular 5-HT(4(b)) mRNA was increased by four times in 20 failing human hearts compared with five donor hearts. 5-HT increased contractile force maximally by 16% (EC(50)=890 nM) and PKA activity by 20% of the effects of (-)-isoproterenol (200 microM) in ventricular trabeculae from new-born piglets in the presence of the phosphodiesterase-inhibitor 3-isobutyl-1-methylxanthine. In ventricular trabeculae from adult pigs (3-isobutyl-1-methylxanthine present) 5-HT increased force by 32% (EC(50)=60 nM) and PKA activity by 39% of (-)-isoproterenol. In right and left ventricular trabeculae from failing hearts, exposed to modified Krebs solution, 5-HT produced variable increases in contractile force in right ventricular trabeculae from 4 out of 6 hearts and in left ventricular trabeculae from 3 out of 3 hearts- range 1-39% of (-)-isoproterenol, average 8%. In 11 left ventricular trabeculae from the failing hearts of four beta-blocker-treated patients, pre-exposed to a relaxant solution with 0.5 mM Ca(2+) and 1.2 mM Mg(2+) followed by a switch to 2.5 mM Ca(2+) and 1 mM Mg(2+), 5-HT (1-100 microM, 3-isobutyl-1-methylxanthine present) consistently increased contractile force and hastened relaxation by 46% and 25% of (-)-isoproterenol respectively. 5-HT caused arrhythmias in three trabeculae from 3 out of 11 patients. In the absence of phosphodiesterase inhibitor, 5-HT increased force in two trabeculae, but not in another six trabeculae from 4 patients. All 5-HT responses were blocked by 5-HT(4) receptor antagonists. We conclude that phosphodiesterase inhibition uncovers functional ventricular 5-HT(4) receptors, coupled to a PKA pathway, through which 5-HT enhances contractility, hastens relaxation and can potentially cause arrhythmias.
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PMID:Functional serotonin 5-HT4 receptors in porcine and human ventricular myocardium with increased 5-HT4 mRNA in heart failure. 1536 89

The objective of this study was to determine the vasodilating effect of 3beta-hydroxy-5-spirostene (diosgenin), a phytoestrogen found in wild yams, using porcine resistance left anterior descending coronary artery. In 5-hydroxytryptamine (3 microM) pre-contracted preparation, diosgenin caused a concentration-dependent (0.01 to 1 microM), endothelium-independent relaxation, with a maximum relaxation of approximately 72% at 1 microM. No apparent effect was observed with 17beta-oestradiol and progesterone with concentrations < or =0.3 microM, and a relaxation of approximately 15% and approximately 23% caused by 17beta-oestradiol (1 microM) and progesterone (1 microM), respectively. Diosgenin-elicited relaxation was not altered by 7alpha,17beta-[9[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diol (ICI 182,780), mifepristone, (+)-bicuculline, cis-N-(2-phenylcyclopentyl)azacyclotridec-1-en-2-amine (MDL 12330A), glibenclamide and scavengers of reactive oxygen species. The iberiotoxin-sensitive, Ca2+-activated K+ (BK(Ca)) current of single vascular myocytes recorded, using patch-clamp techniques, was markedly enhanced by diosgenin, 17beta-oestradiol and progesterone. Application of (9S, 10R, 12R)-2,3,9,10,11,12-hexahydro-10-methoxy-2,9-dimethyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid methyl ester (KT 5823, 300 nM) eradicated the enhancement of BK(Ca) amplitude. Diosgenin, 17beta-oestradiol and progesterone did not affect whereas phloretin, biochanin A and zearalanone (1 microM each) significantly suppressed [Ca2+]o-induced contraction. In oestrogen competition essay using human breast cancer cell (MCF-7 cells), diosgenin (0.001 nM to 10 microM) did not interact with oestrogen receptor-alpha, and no displacement of [3H]17beta-oestradiol was observed. In oestrogen receptor alpha- and beta-fluorescence polarization competitor assay, diosgenin (100 microM) demonstrated a greater competition with the beta-isoform of oestrogen receptor. These results suggest that diosgenin caused an acute, endothelium-independent coronary artery relaxation via protein kinase G signalling cascade and an activation of BK(Ca) channel of arterial smooth muscle cells. The oestrogen receptor (alpha and beta-isoforms) and progesterone receptor are probably not involved.
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PMID:Activation of iberiotoxin-sensitive, Ca2+-activated K+ channels of porcine isolated left anterior descending coronary artery by diosgenin. 1546 98

Low concentrations of genistein enhance the vasodilatation induced by endothelium-independent vasodilators. The present study examined whether or not low concentrations of genistein modulate contractions in isolated porcine coronary arteries. The role of second messengers in the response to genistein was also assessed. Arterial rings were studied in organ baths and contracted with KCl, U-46619 (9,11-dideoxy-9alpha, 11alpha-methanoepoxy prostaglandin F2alpha), 5-hydroxytryptamine (5-HT) or endothelin-1 in the absence or presence of genistein (< or =3 microM). Genistein significantly reduced agonist-induced but not KCl-induced contraction. Inhibition of endothelial nitric oxide synthase and disruption of endothelial function by Triton-X100 did not affect the modulation of contraction by genistein. The genistein-induced attenuation of contraction could be mimicked by both cAMP and cGMP analogs. However, only the cAMP-dependent protein kinase inhibitor, Rp-8-Br-cAMPS, abolished the effect of genistein. These results suggest that genistein reduces agonist-induced contraction by an endothelium-independent manner. This action is mediated via the cAMP-dependent signal transduction pathway.
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PMID:Genistein reduces agonist-induced contractions of porcine coronary arterial smooth muscle in a cyclic AMP-dependent manner. 1549 11

(S)-adenosylmethionine (SAM) is a critical element of melatonin synthesis as the methyl donor in the last step of the pathway, the O-methylation of N-acetyl 5-hydroxytryptamine by hydroxyindole-O-methyltransferase. The activity of the enzyme that synthesizes SAM, methionine adenosyltransferase (MAT), increases 2.5-fold at night in the pineal gland. In this study, we found that pineal MAT2A mRNA and the protein it encodes, MAT II, also increase at night, suggesting that the increase in MAT activity is caused by an increase in MAT II gene products. The night levels of MAT2A mRNA in the pineal gland were severalfold higher than in other neural and non-neural tissues examined, consistent with the requirement for SAM in melatonin synthesis. Related studies indicate that the nocturnal increase in MAT2A mRNA is caused by activation of a well described neural pathway that mediates photoneural-circadian regulation of the pineal gland. MAT2A mRNA and MAT II protein were increased in organ culture by treatment with norepinephrine (NE), the sympathetic neurotransmitter that stimulates the pineal gland at night. NE is known to markedly elevate pineal cAMP, and here it was found that cAMP agonists elevate MAT2A mRNA levels by increasing MAT2A mRNA synthesis and that drugs that block cAMP activation of cAMP dependent protein kinase block effects of NE. Therefore, the NE-cAMP dependent increase in pineal MAT activity seems to reflect an increase in MAT II protein, which occurs in response to cAMP-->protein kinase-dependent increased MAT2A expression. The existence of this MAT regulatory system underscores the importance that MAT plays in melatonin biogenesis. These studies also point to the possibility that SAM production in other tissues might be regulated through cAMP.
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PMID:Methionine adenosyltransferase:adrenergic-cAMP mechanism regulates a daily rhythm in pineal expression. 1550 33

Using whole-cell patch-clamp methods, we examined the hypothesis that serotonin [5-hydroxytryptamine (5-HT)] receptor activation enhances TRPV1 function in mouse colon sensory neurons in lumbosacral dorsal root ganglia, which were identified by retrograde labeling with DiI (1,1'-dioctadecyl-3,3,3',3-tetramethlindocarbocyanine methanesulfonate) injected into multiple sites in the wall of the descending colon. 5-HT increased membrane excitability at a temperature below body temperature in response to thermal ramp stimuli in colon sensory neurons from wild-type mice, but not from TRPV1 knock-out mice. 5-HT significantly enhanced capsaicin-, heat-, and proton-evoked currents with an EC50 value of 2.2 microm. 5-HT (1 microm) significantly increased capsaicin-evoked (100 nm) and proton-evoked (pH 5.5) currents 1.6- and 4.7-fold, respectively, and significantly decreased the threshold temperature for heat current activation from 42 to 38 degrees C. The enhancement of TRPV1 by 5-HT was significantly attenuated by selective 5-HT2 and 5-HT4 receptor antagonists, but not by a 5-HT3 receptor antagonist. In support, 5-HT2 and 5-HT4 receptor agonists mimicked the facilitating effects of 5-HT on TRPV1 function. Downstream signaling required G-protein activation and phosphorylation as intracellularly administered GDP-beta-S [guanosine 5'-O-(2-thiodiphosphate], protein kinase A inhibitors, and an A-kinase anchoring protein inhibitor significantly blocked serotonergic facilitation of TRPV1 function; 5-HT2 receptor-mediated facilitation was also inhibited by a PKC inhibitor. We conclude that the facilitation of TRPV1 by metabotropic 5-HT receptor activation may contribute to hypersensitivity of primary afferent neurons in irritable bowel syndrome patients.
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PMID:TRPV1 function in mouse colon sensory neurons is enhanced by metabotropic 5-hydroxytryptamine receptor activation. 1550 39

Clozapine is an atypical antipsychotic that has a unique clinical profile that distinguishes it from other typical and atypical antipsychotics. At present, the underlying mechanisms of action of clozapine are unclear. Recent studies in the field of schizophrenia suggest that compounds that potentiate N-methyl-d-aspartate (NMDA) receptor function in the appropriate brain regions might be an effective antipsychotic agent. One relevant region in which NMDA receptors play a key role in mediating neurotransmission is the nucleus accumbens. Therefore, we investigated the regulation of NMDA receptor currents and excitatory postsynaptic currents (EPSCs) by clozapine in nucleus accumbens neurons. Whole-cell patch-clamp recordings were performed in rat brain slices. We demonstrate that bath application of clozapine but not haloperidol or the selective 5-hydroxytryptamine 2A antagonist MDL100907 [(R)-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluoro-phenyl)ethyl]-4-piperidine methanol] induces a robust potentiation of NMDA-evoked currents and of glutamatergic EPSCs and that this potentiation is dependent on dopamine release and postsynaptic activation of D1 receptors. Furthermore, the effect of clozapine is selective for NR2B subtype-containing NMDA receptors and is blocked by the selective Src family kinase inhibitor PP2 [4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine] and the protein kinase A-selective inhibitor N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide but not by the protein kinase C-selective inhibitor bisindolylmaleimide I. This effect of clozapine in the nucleus accumbens might underlie the unique clinical profile of this atypical antipsychotic and provides a basis for novel treatment approaches.
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PMID:Clozapine potentiation of N-methyl-D-aspartate receptor currents in the nucleus accumbens: role of NR2B and protein kinase A/Src kinases. 1565 39

Motoneurons require neurotrophic factors for their survival and their differentiation. Xaliproden (SR57746A) is a synthetic compound that exhibits in vivo and in vitro neurotrophic effects in several experimental studies. Here we demonstrate that neuroprotective effects of Xaliproden on motoneuron cultures are mediated by the activation of the mitogen activated protein kinase pathway. It is inhibited by PD98059, a selective and irreversible inhibitor of MEK1. The activation of this pathway seems to involve two different proteins, the protein kinase C and the Ras. Indeed, we show that Xaliproden is able to activate the MAP kinases ERK1/2 and PKC in motoneurons. In addition, the use of a 5-hydroxytryptamine 1A receptor antagonist, Pindobind and pertussis toxin, inhibits the effect of Xaliproden on motoneuron survival, suggesting the involvement of this G-protein coupled receptor. Morever, 8-OH-DPAT, an agonist of 5-hydroxytryptamine 1A receptor, increases the survival of mouse motoneurons but not by the same extent as BDNF or xaliproden. Since 8-OH-DPAT does not act synergistically with Xaliproden, it is likely that their neuroprotective properties involve a similar pathway. Taken together, these results indicate that neuroprotective effects of Xaliproden on mouse motoneurons are dependent on the mitogen-activated protein kinase activation via 5-hydroxytryptamine 1A receptor.
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PMID:MAPK activation via 5-hydroxytryptamine 1A receptor is involved in the neuroprotective effects of xaliproden. 1569 8

Presynaptic, plasma membrane serotonin (5-hydroxytryptamine; 5-HT) transporters (SERTs) clear 5-HT following vesicular release and are regulated through trafficking-dependent pathways. Recently, we provided evidence for a trafficking-independent mode of SERT regulation downstream of adenosine receptor (AR) activation that is sensitive to p38 MAPK inhibitors. Here, we probe this pathway in greater detail, demonstrating elevation of 5-HT transport by multiple p38 MAPK activators (anisomycin, H(2)O(2), and UV radiation), in parallel with p38 MAPK phosphorylation, as well as suppression of anisomycin stimulation by p38 MAPK siRNA treatments. Studies with transporter-transfected Chinese hamster ovary cells reveal that SERT stimulation is shared with the human norepinephrine transporter but not the human dopamine transporter. Saturation kinetic analyses of anisomycin-SERT activity reveal a selective reduction in 5-HT K(m) supported by a commensurate increase in 5-HT potency (K(i)) for displacing surface antagonist binding. Anisomycin treatments that stimulate SERT activity do not elevate surface SERT surface density whereas stimulation is lost with preexposure of cells to the surface-SERT inactivating reagent, 2-(trimethylammonium)ethyl methane thiosulfonate. Guanylyl cyclase (1H-(1,2,4)-oxadiazolo[4,3-a]-quinoxalin-1-one) and protein kinase G inhibitors (H8, DT-2) block AR stimulation of SERT yet fail to antagonize SERT stimulation by anisomycin. We thus place p38 MAPK activation downstream of protein kinase G in a SERT-catalytic regulatory pathway, distinct from events controlling SERT surface density. In contrast, the activity of protein phosphatase 2A inhibitors (fostriecin and calyculin A) to attenuate anisomycin stimulation of 5-HT transport suggests that protein phosphatase 2A is a critical component of the pathway responsible for p38 MAPK up-regulation of SERT catalytic activity.
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PMID:p38 MAPK activation elevates serotonin transport activity via a trafficking-independent, protein phosphatase 2A-dependent process. 1572 87


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