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)

Signaling pathways responsible for serotonin (5-HT)-mediated induction of early response genes prostaglandin G/H synthase-2 (PGHS-2, cyclooxygenase-2) and egr-1 were investigated in rat mesangial cells. Gene induction by 5-HT was dependent on 5-HT2A receptors that were pertussis toxin insensitive indicating coupling to a G-protein of the Gq family. Binding of 5-HT to this receptor activates phosphatidylinositol-specific phospholipase C (PLC) and release of Ca2+ from internal stores, but this activation was not related to PGHS-2 mRNA expression. Similarly, PI-3 kinase was not involved in 5-HT signaling. Instead, inhibition of phosphatidylcholine-specific PLC interfered with PGHS-2 and egr-1 mRNA induction, suggesting this enzyme as a link between 5-HT2A receptors and protein kinase C, an essential part of 5-HT-mediated signaling. The MAP kinase pathway was identified as common signaling pathway of 5-HT or phorbol ester-induced gene expression. Increase of intracellular cAMP by forskolin or dibutyryl cAMP did not induce PGHS-2 or egr-1 mRNA expression by itself, but strongly inhibited 5-HT-mediated mRNA induction. PGHS-2 mRNA and protein induction by 5-HT was also abolished by chelation of Ca2+ ions by EGTA, suggesting involvement of Ca2+-dependent enzymes. In contrast, egr-1 mRNA expression was superinduced in the presence of EGTA. Induction of Egr-1 protein was not changed by EGTA hinting to Ca2+-sensitive posttranscriptional steps. Activation of the Gq-coupled 5-HT2A receptor thus leads to the expression of the early response genes PGHS-2 and egr-1, using common as well as differing signaling elements that allow differential regulation of the expression of these genes that are functionally related to renal hemodynamics and proliferation of mesangial cells, respectively.
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PMID:Signaling pathways mediating induction of the early response genes prostaglandin G/H synthase-2 and egr-1 by serotonin via 5-HT2A receptors. 957 79

There are many examples of a single receptor coupling directly to more than one cellular signal transduction pathway. Although traditional receptor theory allows for activation of multiple cellular effectors by agonists, it predicts that the relative degree of activation of each effector pathway by an agonist (relative efficacy) must be the same. In the current experiments, we demonstrate that agonists at the human serotonin2A (5-HT2A) and 5-HT2C receptors activate differentially two signal transduction pathways independently coupled to the receptors [phospholipase C (PLC)-mediated inositol phosphate (IP) accumulation and phospholipase A2 (PLA2)-mediated arachidonic acid (AA) release]. The relative efficacies of agonists differed depending on which signal transduction pathway was measured. Moreover, relative to 5-HT, some 5-HT2C agonists (e.g., 3-trifluoromethylphenyl-piperazine) preferentially activated the PLC-IP pathway, whereas others (e.g., lysergic acid diethylamide) favored the PLA2-AA pathway. In contrast, when two dependent responses were measured (IP accumulation and calcium mobilization), agonist relative efficacies were not different. These data strongly support the hypothesis termed "agonist-directed trafficking of receptor stimulus" recently proposed by Kenakin [Trends Pharmacol Sci 16:232-238 (1995)]. Concentration-response curves to 5-HT2C agonists were fit well by a three-state model of receptor activation, suggesting that two active receptor states may be sufficient to explain pathway-dependent agonist efficacy. Rational drug design that optimizes preferential effector activity within a group of receptor-selective drugs holds the promise of increased selectivity in clinically useful agents.
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PMID:Effector pathway-dependent relative efficacy at serotonin type 2A and 2C receptors: evidence for agonist-directed trafficking of receptor stimulus. 965 94

The literature describing the expression of 5-HT receptor subtypes by astrocytes is controversial and incomplete. It is clear that primary cultures of astrocytes express receptors of the 5-HT2 family coupled to phospholipase C and of the 5-HT7 receptor family positively coupled to adenylyl cyclase. Cultured astrocytes have also been reported to express receptors of the 5-HT1 family, although the exact subtypes present are unknown. In the present study we have investigated which of the known rat G-protein coupled 5-HT receptor mRNAs are expressed by cultured astrocytes. Reverse transcriptase-polymerase chain reaction (RT-PCR) revealed expression of 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1F, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT5B, 5-HT6 and 5-HT7 receptor mRNAs in astrocytes derived from 2-day old rats and cultured for 10-12 days. Messenger RNAs for 5-HT4 and 5-HT5A receptors were not detected. The functional expression of 5-HT1 receptor subtypes was investigated by measuring the ability of 5-HT1 receptor agonists: 8-OH-DPAT (5-HT1A receptors), RU24969 (5-HT1A, 5-HT1B, 5-HT1D, and 5-HT1F receptors) or sumatriptan (5-HT1B, 5-HT1D, and 5-HT1F receptors) to modulate forskolin or isoproterenol stimulated cAMP production. These compounds, at concentrations up to 10 microM, did not significantly attenuate cAMP production. These results indicate that although astrocytes express mRNA for each of the five 5-HT1 receptor subtypes which have been isolated from the rat, these receptors are not coupled to the inhibition of adenylyl cyclase.
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PMID:Cultured astrocytes express messenger RNA for multiple serotonin receptor subtypes, without functional coupling of 5-HT1 receptor subtypes to adenylyl cyclase. 979 56

Previous studies have shown that rat retinal pigment epithelial (RPE) cells in culture express 5-HT2-type serotonin receptors coupled to phospholipase C activity. The presented data confirm this observation where it is shown that serotonin induced increases in radioactive inositol phosphates accumulation in RPE cells pretreated with tritiated inositol. This increase was significantly (p < 0.01) attenuated by 1 microM spiperone, ketanserin, mesulergine and metergoline while the same concentration of spiroxatrine or yohimbine had no effect, suggesting the involvement of 5-HT2A receptors. Using reverse transcriptase-polymerase chain reaction the presence of 5-HT2A receptor mRNA was demonstrated in total RNA isolated from rat RPE cell cultures. Amplification of a 5-HT2A receptor mRNA-derived product was additionally confirmed by Southern blot analysis. The combined data demonstrates the existence of functional 5-HT2A receptors in rat RPE cells.
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PMID:Serotonin-2A receptor mRNA expression in rat retinal pigment epithelial cells. 983 16

In recent years there have been remarkable developments toward the understanding of the molecular and/or cellular changes in the neuronal second-messenger pathways during ethanol dependence. In general, it is believed that the cyclic adenosine 3',5'-monophosphate (cAMP) and the phosphoinositide (PI) signal-transduction pathways may be the intracellular targets that mediate the action of ethanol and ultimately contribute to the molecular events involved in the development of ethanol tolerance and dependence. Several laboratories have demonstrated that acute ethanol exposure increases, whereas protracted ethanol exposure decreases, agonist-stimulated adenylate cyclase activity in a variety of cell systems, including the rodent brain. Recent studies indicate that various postreceptor events of the cAMP signal transduction cascade (i.e., Gs protein, protein kinase A [PKA], and cAMP-responsive element binding protein [CREB]) in the rodent brain are also modulated by chronic ethanol exposure. The PI signal-transduction cascade represents another important second-messenger system that is modulated by both acute and chronic ethanol exposure in a variety of cell systems. It has been shown that protracted ethanol exposure significantly decreases phospholipase C (PLC) activity in the cerebral cortex of mice and rats. The decreased PLC activity during chronic ethanol exposure may be caused by a decrease in the protein levels of the PLC-beta 1 isozyme but not of PLC-delta 1 or PLC-gamma 1 isozymes in the rat cerebral cortex. Protein kinase C (PKC), which is a key step in the PI-signaling cascade, has been shown to be altered in a variety of cell systems by acute or chronic ethanol exposure. It appears from the literature that PKC plays an important role in the modulation of the function of various neurotransmitter receptors (e.g., gamma-aminobutyrate type A [GABAA], N-methyl-D-aspartate [NMDA], serotonin2A [5-HT2A], and 5-HT2C, and muscarinic [m1] receptors) resulting from ethanol exposure. The findings described in this review article indicate that neuronal-signaling proteins represent a molecular locus for the action of ethanol and are possibly involved in the neuro-adaptational mechanisms to protracted ethanol exposure. These findings support the notion that alterations in the cAMP and the PI-signaling cascades during chronic ethanol exposure could be the critical molecular events associated with the development of ethanol dependence.
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PMID:Neuronal signaling systems and ethanol dependence. 988 43

5-HT2B receptors, in addition to phospholipase C stimulation, are able to trigger activation of the proto-oncogene product p21ras. During mouse embryogenesis, a peak of 5-HT2B receptor expression is detected at the neurulation stage; we localized the 5-HT2B expression in neural crest cells, heart myocardium, and somites. The requirement for functional 5-HT2B receptors shortly after gastrulation, is supported by culture of embryos exposed to 5-HT2B-high affinity antagonist such as ritanserin, which induces morphological defects in the cephalic region, heart and neural tube. Functional 5-HT2B receptors are also expressed during the serotonergic differentiation of the mouse F9 teratocarcinoma-derived clonal cell line 1C11. Upon 2 days of induction by cAMP, 5-HT2B receptors become functional, and on day 4, the appearance of 5-HT2A receptors coincides with the onset of active serotonin transporter by these cells. Active serotonin uptake is modulated by serotonin suggesting autoreceptor functions for 5-HT2B receptors.
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PMID:Mouse 5-HT2B receptor-mediated serotonin trophic functions. 992 40

There is now considerable evidence that a single receptor subtype can couple to multiple effector pathways within a cell. Recently, Kenakin proposed a new concept, termed "agonist-directed trafficking of receptor stimulus", that suggests that agonists may be able to selectively activate a subset of multiple signaling pathways coupled to a single receptor subtype. 5-HT2A and 5-HT2C receptors couple to phospholipase C-(PLC) mediated inositol phosphate (IP) accumulation and PLA2-mediated arachidonic acid (AA) release. Relative efficacies of agonists (referenced to 5-HT) differed depending upon whether IP accumulation or AA release was measured. For the 5-HT2C receptor system, some agonists (e.g. TFMPP) preferentially activated the PLC-IP pathway, whereas others (e.g. LSD) favored PLA2-AA. As expected, EC50's of agonists did not differ between pathways. For the 5-HT2A receptor system, all agonists tested had greater relative efficacy for PLA2-AA than for PLC-IP. In contrast, relative efficacies were not different for 5-HT2A agonists when sequential effects in a pathway were measured (IP accumulation vs. calcium mobilization). These data strongly support the agonist-directed trafficking hypothesis.
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PMID:Pleiotropic behavior of 5-HT2A and 5-HT2C receptor agonists. 992 46

The mitogen-activated protein kinase (MAPK) pathway, classically associated with cell growth and dependent on tyrosine kinases such as MAPK kinase (MEK), can modulate smooth muscle contractility, and our laboratory has tested the hypothesis that 5-HT can activate the MAPK pathway in arterial smooth muscle through activation of a 5-HT2A receptor. Tyrosine kinase inhibitors including genistein and the specific MEK inhibitor PD098059, but not the inactive tyrosine kinase congener daidzein reduced and shifted 5-HT-induced contraction rightward in isolated, endothelium-denuded rat arteries. Activation of a tyrosine kinase/MEK via the 5-HT2A receptor was partially independent of two major signaling pathways typically associated with the 5-HT2A receptor--activation of L-type voltage gated calcium channels and phospholipase C. Western analyses using antibodies directed against tyrosyl-phosphorylated-, activated Erk MAPK, and MEK proteins from cultured aortic smooth muscle cells demonstrated that 5-HT activated MEK and the Erk MAPKs in a time-, concentration-, receptor- and tyrosine kinase-dependent manner. Taken together, these findings provide evidence for a novel pathway of vascular signal transduction--activation of the MAPK pathway--for the 5-HT2A receptor.
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PMID:Activation of the mitogen-activated protein kinase pathway via the 5-HT2A receptor. 992 53

5-Hydroxytryptamine 5-HT2A and 5-HT2C receptors share many properties, including a common ability to stimulate phospholipase C. Traditionally, this activation was thought to be initiated only after agonist binding, in accordance with the ternary complex model of receptor function. Recently, though, the 5-HT2C receptor was shown to deviate from this tenet by spontaneously isomerizing into the active receptor state, thereby activating G proteins in the absence of agonist. To determine if 5-HT2A receptors share this property of constitutive activity, 5-HT2A and 5-HT2C receptor function was evaluated in transiently transfected NIH 3T3 fibroblasts. In 3T3 cells expressing 5-HT2C receptors, agonist-independent phosphatidyl inositol hydrolysis was substantially elevated relative to mock-transfected cells. In contrast, expression of the 5-HT2A receptor at the same density caused only a marginal increase in basal signaling. Control experiments in the current and previous papers establish that basal activity does not reflect contaminating serotonin. In addition, the magnitude of serotonin-induced signaling was the same in cells expressing either receptor, suggesting that the intrinsic ability of the two receptors to couple to G proteins is comparable. These data indicate that the 5-HT2A receptor has a much lower intrinsic ability to spontaneously adopt or maintain the active receptor conformation than does the closely related 5-HT2C receptor.
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PMID:Differences in agonist-independent activity of 5-Ht2A and 5-HT2c receptors revealed by heterologous expression. 993 46

The effect of 5-hydroxytryptamine (5-HT) on phospholipase C (PLC)-mediated phosphoinositide (PI) hydrolysis and intracellular Ca2+ ([Ca2+]i) changes was investigated in canine cultured aorta smooth muscle cells (ASMCs). 5-HT-stimulated inositol phosphate (IP) accumulation was time and concentration dependent with a half-maximal response (pEC50) and a maximal response at 6.4 and 10 microM, n = 6, respectively. Stimulation of ASMCs by 5-HT produced an initial transient peak followed by a sustained, concentration-dependent elevation in [Ca+]i. The half-maximal response (pEC50) values of 5-HT for the peak and sustained plateau were 7.1 and 6.9, respectively. Ketanserin and mianserin (1 and 3 nM), 5-HT2A antagonists, were equipotent and had high affinity in antagonising the 5-HT-induced IP accumulation and [Ca2+]i change with pK(B) values of 8.6-9.1 and 8.6-9.4, respectively. In contrast, the concentration-effect curves of 5-HT-induced IP and [Ca2+]i responses were not shifted until the concentrations of NAN-190 and metoctopramide (5-HT1A and 5-HT3 receptor antagonists, respectively) were increased to as high as 1 microM with pK(B) values of 5.7-6.3 and 6.1-6.6, respectively, indicating that the 5-HT receptor-mediated responses had low affinity for these antagonists. Pre-treatment of ASMCs with pertussis toxin (100 ng/mL, 24 h) caused a significant inhibition of 5-HT-induced IP accumulation and [Ca2+]i change in ASMCs. Depletion of external Ca2+ or removal of Ca2+ by addition of EGTA led to a significant attenuation of IP accumulation and [Ca2+]i change induced by 5-HT. Influx of external Ca2+ was required for the 5-HT-induced responses, because Ca2+-channel blockers--verapamil, nifedipine and Ni2+--partly inhibited the 5-HT-induced IP accumulation and Ca2+ mobilisation. The sustained elevation of [Ca2+]i response to 5-HT was dependent on the presence of external Ca2+. Removal of external Ca2+ by addition of 5 mM EGTA during the sustained phase caused a rapid decline in [Ca2+]i to lower than the resting level. The sustained elevation of [Ca2+]i could then be evoked by addition of 1.8 mM Ca2+ in the continued presence of 5-HT. These results demonstrate that 5-HT directly stimulates PLC-mediated PI hydrolysis and Ca2+ mobilisation, at least in part, through a pertussis toxin-sensitive G protein in canine ASMCs. 5-HT2A receptors may be predominantly mediating IP accumulation, and subsequently IP-induced Ca2+ mobilisation may function as the transducing mechanism for 5-HT-stimulated contraction of aorta smooth muscle.
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PMID:5-Hydroxytryptamine-induced phosphoinositide hydrolysis and Ca2+ mobilisation in canine cultured aorta smooth muscle cells. 1037 10


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