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:3.1.4.3 (phospholipase C)
18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Ca2+ channel antagonists nifedipine and verapamil each significantly inhibited (50-100%) the smooth muscle contraction induced in response to either 5-hydroxytryptamine (1 microM, 5-HT) or 20 mM K+ (K(+)-physiological salt solution) in the basilar artery. Simultaneous measurements of smooth muscle membrane potential showed that changes in potential were not modified at this time. A similar inhibitory action against the smooth muscle contraction but not the depolarization to 5-HT was obtained with the putative protein kinase C and phospholipase C inhibitors, 1-(5-isoquinolinesulphonyl)-2-methylpiperazine (10 microM, H7) and 2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate (70 microM, NCDC). These data indicate that 5-HT-induced Ca2+ influx through voltage sensitive channels is important for smooth muscle contraction but not depolarization in the rabbit basilar artery.
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PMID:Ca2+ channel antagonists and inhibition of protein kinase C each block contraction but not depolarization to 5-hydroxytryptamine in the rabbit basilar artery. 851 72

Parafollicular (PF) cells secrete 5-hydroxytryptamine in response to increased extracellular Ca2+ ([Ca2+]e). This stimulus causes Cl- channels in PF secretory vesicles to open, leading to vesicle acidification. PF cells express a plasmalemmal heptahelical receptor (CaR) that binds Ca2+, Gd3+, and Ba2+. We now report that the CaR mediates vesicle acidification. Ca2+, Gd3+, and Ba2+ induced vesicle acidification, which was independent of channel-mediated Ca2+ entry. Agonist-induced vesicle acidification was blocked by pertussis toxin, inhibitors of phosphatidylinositol-phospholipase C, calmodulin, NO synthase, guanylyl cyclase, or protein kinase G. PF cells contained NO synthase immunoreactivity, and vesicles were acidified by NO donors and dibutyryl cGMP. [Ca2+]e, and Gd3+ mobilized thapsigargin-sensitive internal Ca2+ stores. [35S]G alpha i and [35S]G alpha q were immunoprecipitated from PF membranes incubated with agonists in the presence of [35S]adenosine 5'-O-(thiotriphosphate). Labeling of G alpha i but not G alpha q was antagonized by pertussis toxin. Vesicles acidified in response to activation of protein kinase C; however, protein kinase C inhibition blocked calcium channel- but not CaR-dependent acidification. We propose the following signal transduction pathway: CaR -> Gi -> phosphatidylinositol-phospholipase C -> inositol 1,4,5-trisphosphate -> [Ca2+]i -> Ca2+/calmodulin -> NO synthase -> NO -> guanylyl cyclase -> cGMP -> protein kinase G -> opens vesicular Cl- channel.
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PMID:Acidification of serotonin-containing secretory vesicles induced by a plasma membrane calcium receptor. 862 45

1. Facilitation of the N-methyl-D-aspartate (NMDA) receptor-mediated depolarization of cortical neurones induced by metabotropic glutamate receptor (mGluR) agonists in the presence of tetrodotoxin has been examined by use of grease-gap recording. 2. Quisqualate (1-2 microM) and 10 to 100 microM 1S,3R-I-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) facilitated the NMDA-, but not the kainate-induced depolarization with an EC50 of 16 microM for 1S,3R-ACPD. The facilitation induced by quisqualate was reduced, but not blocked, by 4 microM 6-cyano-7-nitroquinoxaline-2,3-dione. 3. D,L-2-Amino-3-phosphonopropionic acid and D,L-2-amino-4-phosphonobutyric acid antagonized the 1S,3R-ACPD facilitation in a non-competitive manner with IC50 values of 0.24 microM and 4.4 microM respectively. 4. Homologous desensitization of the 1S,3R-ACPD induced facilitation was not observed. The facilitation was not altered by 10 nM staurosporine or 3 microM phorbol diacetate. 5. Substitution of 20 microM 8-bromo-cyclic adenosine monophosphate, 20 microM 8-bromo-cyclic guanosine monophosphate, or 10 microM arachidonic acid for 1S,3R-ACPD did not induce facilitation of the NMDA response. However, the 1S,3R-ACPD facilitation was potentiated by 10 mM myo-inositol and exhibited heterologous desensitization following exposure to 100 microM 5-hydroxytryptamine. 6. The 1S,3R-ACPD-induced facilitation persisted in both 10 microM nifedipine and nominally Ca(2+)-free medium and was only gradually eliminated following addition of 100 microM bis-(-o-aminophenoxy)-ethane-N,N,N,N-tetraacetic acid in Ca(2+)-free medium. Facilitation of the NMDA response induced by carbachol, but not phenylephrine, was also observed in nominally Ca(2+)-free medium. Perfusing 50 microM bis-(-aminophenoxy)-ethane-N,N,N,N-tetraacetic acid aminoethoxy eliminated the 1S,3R-ACPD facilitation. 7. These experiments have shown that mGluR agonists selectively facilitate the NMDA depolarization of cortical wedges, most likely by activating one or more mGluR subtypes that couple to phospholipase C. We conclude the facilitation results from a Ca(2+)-sensitive mechanism dependent on activation of phospholipase C and release of internal Ca2+. The facilitation is not contingent on activation of protein kinase C or entry of Ca2+ through nifedipine-sensitive Ca2+ channels.
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PMID:Characterization of metabotropic glutamate receptor-mediated facilitation of N-methyl-D-aspartate depolarization of neocortical neurones. 864 13

1. Chinese hamster ovary cells (CHO-K1) express an endogenous 5-hydroxytryptamine (5-HT)1B-like receptor that is negatively coupled to adenylyl cyclase through a pertussis toxin (PTX)-sensitive mechanism. Furthermore, the human adenosine A1 receptor when expressed in CHO-K1 cells (CHO-A1) has been shown to mobilize intracellular Ca2+ through a PTX-sensitive mechanism. Therefore the aim of this investigation was to determine whether the endogenous 5-HT1B-like receptor was able to stimulate increases in intracellular free [Ca2+] ([Ca2+]i) in CHO-A1 cells. 2. In agreement with previous studies using CHO cells, 5-hydroxytryptamine (5-HT) elicited a concentration-dependent inhibition of forskolin-stimulated [3H]-cyclic AMP production in CHO-A1 cells (p[EC50] = 7.73 +/- 0.13). 5-HT (1 microM) inhibited 47 +/- 5% of the [3H]-cyclic AMP accumulation induced by 3 microM forskolin. Forskolin stimulated [3H]-cyclic AMP accumulation was also inhibited by the 5-HT1 receptor agonists (p[EC50] values) 5-carboxyamidotryptamine (5-CT; 8.07 +/- 0.08), RU 24969 (8.12 +/- 0.33) and sumatriptan (5.80 +/- 0.31). 3. 5-HT elicited a concentration-dependent increase in [Ca2+]i in CHO-A1 cells (p[EC50] = 8.07 +/- 0.05). In the presence of 2 mM extracellular Ca2+, 5-HT (1 microM) increased [Ca2+]i from 174 +/- 17 nM to 376 +/- 22 nM. The 5-HT1 receptor agonists (p[EC50] values), 5-carboxyamidotryptamine (5-CT; 7.9 +/- 0.02), RU 24969 (8.1 +/- 0.07) and sumatriptan (5.9 +/- 0.11) all elicited concentration-dependent increases in [Ca2+]i. Similar maximal increases in [Ca2+]i were obtained with each agonist. The selective 5-HT1A receptor agonist, 8-OH-DPAT (10 microM) did not stimulate increases in [Ca2+]i. 5-HT (100 microM) and 5-CT (10 microM) did not stimulate a measurable increase in [3H]-inositol phosphate accumulation in CHO-A1 cells. 4. 5-HT (1 microM)-mediated increases in [Ca2+]i were insensitive to the 5-HT receptor antagonist, ritanserin (5-HT2; 100 nM), ketanserin (5-HT2; 100 nM), LY-278,584 (5-HT3; 1 microM) and WAY 100635 (5-HT1A; 1 microM). The response to 5-HT (100 nM) was antagonized by the non-selective 5-HT1 antagonist, methiothepin (pKb = 8.90 +/- 0.09) and the 5-HT1D antagonist GR 127935 (pKb = 10.44 +/- 0.06). 5. Pretreatment with PTX (200 ng ml-1 for 4 h) completely attenuated the Ca2+ response to 100 microM 5-HT. 6. In untransfected CHO-K1 cells, 5-HT (1 microM), RU 24969 (1 microM), and 5-CT (1 microM) elicited increases in [Ca2+]i similar to those observed in CHO-A1 cells. 7. These data demonstrate that in CHO-K1 cells the endogenously expressed 5-HT1B-like receptor couples to the phospholipase C/Ca2+ signalling pathway through a PTX-sensitive pathway, suggesting the involvement of Gi/Go protein(s).
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PMID:Coupling of an endogenous 5-HT1B-like receptor to increases in intracellular calcium through a pertussis toxin-sensitive mechanism in CHO-K1 cells. 868 Jul 21

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.
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PMID:Regulation of 5-hydroxytryptamine-induced calcium mobilization by cAMP-elevating agents in cultured canine tracheal smooth muscle cells. 876 73

In this study, we quantitate and compare the ability of the 5-hydroxytryptamine 1A (5-HT1A) receptor to modulate the activities of phospholipase C and adenylyl cyclase as a function of receptor concentration. We used a single clonal cell line permanently expressing the human 5-HT1A receptor, and progressively depleted the receptor concentration using an alkylating antagonist (N8-bromoacetyl-N1-3'-(4-indolyloxy)-2'-hydroxypropyl-Z-1,8-diamin o-p-methane, (+-) Pindobind). For serotonin-induced phospholipase C stimulation, reductions in receptor number result in dose-response curves that shift downward and rightward, reflecting both a decreasing maximal effect as well as an increasing ED50. In contrast, depletion of more than 95% of the receptors has no effect on the maximal inhibition of forskolin-stimulated adenylyl cyclase activity. Moreover, at all receptor concentrations, the amount of serotonin required to produce half-maximal phospholipase C stimulation is several-fold more than that required to produce half-maximal inhibition of adenylyl cyclase activity. We conclude that the 5-HT1A receptor modulates these two pathways differently, and that the overall response to challenge with serotonin, in terms of both phosphatidyl inositol hydrolysis and cyclic AMP production, is dependent upon receptor number.
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PMID:The human 5-hydroxytryptamine 1A receptor differentially modulates phospholipase C and adenylyl cyclase activities. 891 40

Stereo-selective calcium antagonistic properties of the enantiomers of lemildipine (CAS 94739-29-4, NB-818) were assessed in vascular tissues, including pig coronary artery and dog cerebral artery. Ca2+ antagonistic action of (-)-lemildipine was about 5 times and 100 times more potent than nifedipine and (+)-lemildipine, respectively. (-), (+), and (+/-)-lemildipine showed a slow onset and long duration of Ca2+ antagonistic action. Pretreatment with (-)-lemildipine and (+/-)-lemildipine for 30 min inhibited the contractions produced by 5-hydroxytryptamine and endothelin-1 with pD2 values between 6.0-8.5, whereas (+)-lemildipine and nifedipine were less potent. Of the lemildipine enantiomers, (+)-lemildipine at a low concentration (1 nmol/l) had a slight but significant Ca2+ agonistic action. However, (+)-lemildipine had no apparent effect on the pCa-tension relationship in the dog basilar artery permeabilized with Staphylococcus aureus alpha-toxin. Enantiomers of lemildipine as well as nifedipine competitively antagonized the specific binding of (+)-[3H]PN 200-110 (isradipine) to the membranes of pig coronary artery in the following order: (-)-lemildipine > nifedipine > (+/-)-lemildipine > (+)-lemildipine. These results suggest that the stereo-selective Ca2+ antagonistic actions of lemildipine enantiomers and nifedipine assessed in the functional experiments were well correlated with their potencies for the competition with the (+)-[3H]PN 200-110 binding to the pig coronary artery.
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PMID:Stereo-selective calcium antagonistic and binding properties of the enantiomers of lemildipine in vascular tissue of pigs and dogs. 895 63

The action of 5-hydroxytryptamine (5-HT) via the 5-HT1A receptor on dissociated rat dorsal raphe neurons was characterized under the whole-cell mode by using the nystatin-perforated patch-clamp technique. Under voltage-clamp conditions, 5-HT induced an inwardly rectifying K+ current (I5-HT) in a concentration-dependent manner. I5-HT was mimicked by 8-OH-DPAT and buspirone, which are both 5-HT1A receptor agonists. I5-HT was reversibly blocked by such 5-HT1A receptor antagonists as (S)-UH-301 a 5-HT4 receptor antagonist. I5-HT was antagonized concentration-dependently by such K+ channel blockers as quinine, Ba2+ and 4-aminopyridine but was relatively insensitive to both CS+ and tetraethylammonium. When the neurons were loaded with guanosine 5'-O-3-thiotriphosphate through a patch pipette, the K+ current induced by 5-HT became irreversible. N-ethylmaleimide (NEM), a sulfhydryl alkylating agent, irreversibly blocked I5-HT. The intracellular perfusion with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), a Ca2+ chelator, or neomycine, a phospholipase C inhibitor, never significantly affected the 5-HT-induced response. 12-Myristate 13-acetate diester (PMA), a protein kinase C (PKC) activator, had only a weak inhibitory effect on I5-HT, and staurosporine, a PKC inhibitor, failed to significantly occlude I5-HT. Therefore, the K+ conductance activated via the 5-HT1a receptor of dorsal raphe neurons was thus characterized by the sensitivity to such K+ channel blockers as quinine, Ba2+ and 4-aminopyridine. Moreover, G protein which is NEM-sensitive and can couple to the 5-HT1A receptor, is thus considered to activate the inwardly rectifying K+ conductance without being mediated by such second messengers as Ca2+ and PKC.
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PMID:Characterization of the K+ current mediated by 5-HT1A receptor in the acutely dissociated rat dorsal raphe neurons. 903 20

The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) elicits a wide array of physiological effects by binding to several receptor subtypes. The 5-HT2 family of receptors belongs to a large group of seven-transmembrane-spanning G-protein-coupled receptors and includes three receptor subtypes (5-HT2A, 5-HT(2B) and 5-HT(2C)) which are linked to phospholipase C, promoting the hydrolysis of membrane phospholipids and a subsequent increase in the intracellular levels of inositol phosphates and diacylglycerol. Here we show that transcripts encoding the 2C subtype of serotonin receptor (5-HT(2C)R) undergo RNA editing events in which genomically encoded adenosine residues are converted to inosines by the action of double-stranded RNA adenosine deaminase(s). Sequence analysis of complementary DNA isolates from dissected brain regions have indicated the tissue-specific expression of seven major 5-HT(2C) receptor isoforms encoded by eleven distinct RNA species. Editing of 5-HT(2C)R messenger RNAs alters the amino-acid coding potential of the predicted second intracellular loop of the receptor and can lead to a 10-15-fold reduction in the efficacy of the interaction between receptors and their G proteins. These observations indicate that RNA editing is a new mechanism for regulating serotonergic signal transduction and suggest that this post-transcriptional modification may be critical for modulating the different cellular functions that are mediated by other members of the G-protein-coupled receptor superfamily.
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PMID:Regulation of serotonin-2C receptor G-protein coupling by RNA editing. 915 85

The unicellular eukaryotic dinoflagellates shed their flagella and form a new pellicle cyst wall in response to environmental stress. This encystment process can also be induced by indoleamines such as melatonin and 5-methoxytryptamine. To decipher the complex signaling events which lead to encystment, we have investigated the functional roles of Ca2+ and inositol phosphates in indoleamine-induced encystment of the dinoflagellates Alexandrium catenella and Crypthecodinium cohnii. Pretreatment with EGTA, but not with EDTA, effectively blocked the indoleamine-induced encystment of A. catenella in a dose-dependent manner. Conversely, agents that facilitate the influx of Ca2+ (Bay K 8644, A23187 and ionomycin) dose-dependently induced encystment of A. catenella. Endoplasmic Ca2+-ATPase inhibitors such as thapsigargin and the peptide toxin melittin also induced encystment of A. catenella. These results suggest that an elevation of intracellular [Ca2+] may be involved in the encystment response. In terms of the regulation of phospholipase C, melatonin dose- and time-dependently stimulated the formation of inositol phosphates in C. cohnii. The rank order of potency for several indoleamines to stimulate inositol phosphates formation was 2-iodomelatonin > 5-methoxytryptamine > or = melatonin >> N-acetylserotonin > 5-hydroxytryptamine. This rank order was the same as for the indoleamine-induced encystment of C. cohnii as previously reported. Our results indicate that indoleamine-induced activation of phospholipase C and elevation of intracellular [Ca2+] may be proximal steps in the signal transduction pathway leading to encystment in dinoflagellates. Moreover, this is the first demonstration of the possible involvement of Ca2+ and inositol phosphates as second messengers in dinoflagellates.
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PMID:Calcium ion dependency and the role of inositol phosphates in melatonin-induced encystment of dinoflagellates. 921 24


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