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 family of serotonin receptors consists of at least eight distinct subtypes, divided into four classes based on their pharmacological and functional characteristics. Here we report the cloning and expression in Swiss 3T3 cells of the human 5-HT2 and 5-HT1A receptor subtypes. Both genes encode functional receptors for 5-HT, that differ considerably in genomic structure, primary amino acid sequence, pharmacology and signal transduction. The 5-HT1A receptor transfectants displayed a single high affinity site for the agonist [3H](+/-)-8-hydroxy-2-(di-n-propylamino)tetralin HBr ([3H]8-OH-DPAT) and a pharmacological profile specific for the 5-HT1A receptor. In these transfectants, 5-HT mediated a dose-dependent inhibition of forskolin-stimulated cAMP levels. Cells expressing the 5-HT2 receptor exhibited high affinity binding for the antagonist [3H]ketanserin with a 5-HT2 receptor specific pharmacological profile. In these cells 5-HT activated phospholipase C in a dose-dependent manner. The 5-HT2 receptor displayed a genomic organization quite different from the 5-HT1A, 5-HT1B and 5-HT1D receptor subtypes. While these receptors are encoded by one single exon, the 5-HT2 receptor is encoded by three exons separated by two introns. The latter finding adds and additional molecular criterion for receptor classification.
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PMID:Genomic organization, coding sequence and functional expression of human 5-HT2 and 5-HT1A receptor genes. 133 Jun 47

Serotonin 5-HT1A receptors have been reported to be negatively coupled to muscarinic receptor-stimulated phosphoinositide turnover in the rat hippocampus. In the present study, we have investigated further the pharmacological specificity of this negative control and attempted to elucidate the mechanism whereby 5-HT1A receptor activation inhibits the carbachol-stimulated phosphoinositide response in immature or adult rat hippocampal slices. Various 5-HT1A receptor agonists were found to inhibit carbachol (10 microM)-stimulated formation of total inositol phosphates in immature rat hippocampal slices with the following rank order of potency (IC50 values in nM): 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (11) greater than ipsapirone (20) greater than gepirone (120) greater than RU 24969 (140) greater than buspirone (560) greater than 1-(m-trifluoromethylphenyl)piperazine (1,500) greater than methysergide (5,644); selective 5-HT1B, 5-HT2, and 5-HT3 receptor agonists were inactive. The potency of the 5-HT1A receptor agonists investigated as inhibitors of the carbachol response was well correlated (r = 0.92) with their potency as inhibitors of the forskolin-stimulated adenylate cyclase in guinea pig hippocampal membranes. 8-OH-DPAT (10 microM) fully inhibited the carbachol-stimulated formation of inositol di-, tris-, and tetrakisphosphate but only partially antagonized (-40%) inositol monophosphate production. The effect of 8-OH-DPAT on carbachol-stimulated phosphoinositide turnover was not prevented by addition of tetrodotoxin (1 microM), by prior destruction of serotonergic afferents, by experimental manipulations causing an increase in cyclic AMP levels (addition of 10 microM forskolin), or by changes in membrane potential (increase in K+ concentration or addition of tetraethylammonium). Prior intrahippocampal injection of pertussis toxin also failed to alter the ability of 8-OH-DPAT to inhibit the carbachol response. Carbachol-stimulated phosphoinositide turnover in immature rat hippocampal slices was inhibited by the protein kinase C activators phorbol 12-myristate 13-acetate (10 microM) and arachidonic acid (100 microM). Moreover, the inhibitory effect of 8-OH-DPAT on the carbachol response was blocked by 10 microM quinacrine (a phospholipase A2 inhibitor) but not by BW 755C (100 microM), a cyclooxygenase and lipoxygenase inhibitor. These results collectively suggest that 5-HT1A receptor activation inhibits carbachol-stimulated phosphoinositide turnover by stimulating a phospholipase A2 coupled to 5-HT1A receptors, leading to arachidonic acid release. Arachidonic acid could in turn activate a gamma-protein kinase C with as a consequence an inhibition of carbachol-stimulated phosphoinositide turnover. This inhibition may be the consequence of a phospholipase C phosphorylation and/or a direct effect on the muscarinic receptor.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Potential mechanisms involved in the negative coupling between serotonin 5-HT1A receptors and carbachol-stimulated phosphoinositide turnover in the rat hippocampus. 184 78

The 5-HT1 receptor family comprises five different pharmacologic subtypes, designated 5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D, and 5-HT1E, whose common property is to bind 5-HT with nanomolar affinity. Recent investigations with molecular biology approaches led to the cloning and sequencing of 5-HT1A receptors in the rat and in the human, and of the 5-HT1C receptor in the rat. Although the 5-HT1A and 5-HT1C protein binding subunits exhibit the same structure with seven hydrophobic transmembrane domains, an extracellular N terminal and an intracellular C tail, their respective amino-acid sequences are markedly different. Indeed, a higher degree of sequence homology is found between the 5-HT1C and 5-HT2 receptors than between the former and 5-HT1A receptors, suggesting that the 5-HT1C subtype in fact belongs to the 5-HT2 class of central 5-HT receptors. All other 5-HT1 receptor subtypes are negatively coupled to adenylyl cyclase, whereas the 5-HT1C subtype, like 5-HT2 receptors, is positively coupled to phospholipase C. The respective regional distributions and regulatory properties, as well as pending questions regarding the ultrastructural localization, synthesis, mutual interactions, and axonal flow of 5-HT1 receptor subtypes, are also discussed.
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PMID:The main features of central 5-HT1 receptors. 207 71

The existence of two different functional receptors for 5-hydroxytryptamine (5-HT) was first proposed by Gaddum and Picarelli. Aided by the development of radioligand binding techniques, the heterogeneity of 5-HT receptors has become more apparent in the past ten years. There are three main types of 5-HT receptors: 5-HT1, 5-HT2 and 5-HT3. Moreover, 5-HT1 is heterogenous and can be divided into 5-HT1A, 5-HT1B, 5-HT1C and 5-HT1D subtypes. 5-HT1B is probably related to the 5-HT autoreceptor controlling 5-HT release. Multiple 5-HT receptors are differentially distributed throughout the brain, and the agonist-receptor interaction is altered by physical parameters and chemicals, suggesting that the receptors may be physiologically relevant. Three 5-HT receptor subtypes, 5-HT1A, 5-HT1C and 5-HT2, have been cloned. All three receptors contain approximately 450 amino acids arrayed as seven transmembrane domains. 5-HT1 and 5-HT1A are coupled to adenylate cyclase positively and negatively, respectively, while 5-HT1C and 5-HT2 are coupled positively to phospholipase C. 5-HT1A is also coupled to the opening of K+ channels in hippocampal pyramidal cells. A number of 5-HT-induced physiological responses have been shown to correlate with the 5-HT receptor subtypes. Based on a number of pharmacological studies, it seems likely that the mode of action of certain psychotropic drugs is closely related to the activity of central 5-HT receptors.
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PMID:[5-Hydroxytryptamine receptors]. 255 57

Growth factors can be divided into two classes which act through distinct signal transduction pathways. One class including epidermal growth factor, platelet derived growth factor and fibroblast growth factor activates receptor tyrosine kinases, and the second class, including thrombin, bombesin, bradykinin and vasopressin activates a phosphoinositide-specific phospholipase C through GTP-binding proteins which can be inactivated by pertussis toxin. In Chinese hamster lung fibroblasts, thrombin-induced mitogenicity seems to correlate well with phospholipase C activation and both events are sensitive to pertussis toxin. Thrombin, like the other mitogens in this class, simultaneously inhibits adenylate cyclase. This involves an inhibitory G protein (Gi), a well established pertussis toxin substrate. The relative contributions of the two signalling pathways to mitogenicity has not been evaluated so far. We report here that the neurotransmitter serotonin (5-hydroxytryptamine), a contracting agent and mitogen for smooth muscle cells, activates phospholipase C, inhibits adenylate cyclase and stimulates DNA synthesis in fibroblasts. These events are sensitive to pertussis toxin. We show that the mitogenicity of 5-hydroxytryptamine can be uncoupled from phospholipase C activation that is mediated by 5-HT2 receptors, but correlates perfectly with inhibition of adenylate cyclase through 5-HT1B receptor. We propose that inhibition of adenylate cyclase or activation of an undefined effector system by Gi is important in 5-hydroxytryptamine induced DNA synthesis and contributes to the strong mitogenicity of the other members of this family of growth factors.
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PMID:Serotonin stimulates DNA synthesis in fibroblasts acting through 5-HT1B receptors coupled to a Gi-protein. 304 68

Serotonin (5-HT) plays important roles in various behavioral and physiological processes in Aplysia californica. These include feeding, locomotion, circadian rhythm, learning and memory, synaptic plasticity, and synaptic growth. Serotonin modulates these various functions by interacting with different 5-HT receptor subtypes that are coupled to various second-messenger systems. We report here the isolation and characterization of the first two serotonergic receptors from Aplysia californica, Ap5-HTB1 and Ap5-HTB2, using a strategy based on the amino acid sequence homology among G-protein-coupled biogenic amine receptors. Ap5-HTB1 and Ap5-HTB2 are both intronless and highly homologous to each other, sharing 79.5% sequence identity at the amino acid level. Sequence comparison reveals that these receptors are 33.1 to 23.3% identical to the following 5-HT receptors: 5-HTdro1 > 5-HT6 > 5-HTlym > mouse 5-HT1B > 5-HTdro2A > mouse 5-HT7 > rat 5-HT2A. Both Ap5-HTB1 and Ap5-HTB2 encode functional 5-HT receptors. When expressed in cultured cells, these receptors stimulate phospholipase C in response to 5-HT in a dose-dependent manner. This stimulation can be blocked by specific 5-HT receptor antagonists. Using RT-PCR and Western blot analysis, we have detected these receptors in the CNS (Ap5-HTB2) and in the reproductive system (Ap5-HTB1). The nucleotide sequences of Ap5-HTB1 and Ap5-HTB2 were submitted to GenBank; the accession numbers are L43557 and L43558, respectively.
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PMID:Cloning and characterization of two related serotonergic receptors from the brain and the reproductive system of Aplysia that activate phospholipase C. 747 9

5-Hydroxytryptamine (5-HT) receptors contain seven putative transmembrane domains and couple via different guanine nucleotide binding proteins to specific effector enzymes. Studies with other receptors identify the second and third intracellular loops or the C-terminus of the receptor as important for selective effector coupling. However, it is not known which regions of the 5-HT receptor determine effector coupling specificity. To address this question, we constructed a chimeric 5-HT receptor in which the third intracellular (i3) loop is derived from the 5-HT2A receptor, which is coupled to activation of phospholipase C, and the rest of the sequence is derived from the 5-HT1B receptor, which is coupled to inhibition of adenylyl cyclase. The chimeric receptor exhibited ligand binding properties similar to those of the 5-HT1B receptor and distinct from those of the 5-HT2A receptor. This suggests that the i3 loop is not critical for the unique pharmacology of the 5-HT1B receptor. In contrast, the chimeric receptor exhibited signaling properties similar to those of the 5-HT2A receptor and distinct from those of the 5-HT1B receptor. This indicates that the i3 loop determines the effector coupling specificity of the 5-HT2A receptor.
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PMID:The third intracellular loop of the 5-hydroxytryptamine2A receptor determines effector coupling specificity. 789 Oct 70

The serotonin (5-HT) is implicated in many centrally-regulated functions and has shown to be involved in affective disorders, such as depression and anxiety disorders. Recent progress in pharmacology and molecular neurobiology have confirmed the concept of the heterogeneity of 5-HT receptors and permitted reformulation of new hypothesis concerning antidepressant mechanisms of action, in particular those concerning serotoninergic receptors. Up to date, among the 5-HT defined sites, only 13 have been cloned, and several subfamilies have been described. Particularly, the 5-HT1 family containing receptors: 5-HT1A, 5-HT1B/1D, 5-HT1E and 5-HT1F. The 5-HT2 family includes receptors that stimulate phospholipase C: 5-HT2A (previously termed 5-HT2), 5-HT2B and 5-HT2C (previously termed 5-HT1C). Concerning 5-HT2 family, it is possible that some 5-HT binding drugs properties initially attributed to 5-HT2A receptors, might well be mediated by 5-HT2C receptors. Recently, medifoxamine (Cledial) activities on 5-HT systems have been shown. In particular, these activities are related on 5-HT2C and/or 5-HT2A binding sites. Results indicate that, in vitro, medifoxamine affinities (Ki) are near to 1 microM, for both 5-HT2C and 5-HT2A sites (ratio = 1.42). On the other hand, m-CPP, an 5-HT2C agonist, considered as a reference compound, has the same affinities that medifoxamine, but a higher one for 5-HT2A (ratio = 3.42). In animals models considered as predictive for psychotropic activity in human, we investigate in rat the impact of medifoxamine on 5-HT2C receptors, using Learned-Helplessness model (LH) and the social interaction test.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[The role of type 2 serotonin receptors, 5-HT2A and 5-HT2C, in depressive disorders: effect of medifoxamine]. 798 7

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 effect of Gi coupled receptor activation (adenosine A1 and 5-HT1B receptors) on cholecystokinin receptor-stimulated inositol phosphate accumulation has been investigated in Chinese hamster ovary cells transfected with the human adenosine A1 receptor cDNA (CHO-A1). CHO cells constitutively express the 5-HT1B receptor [Berg, Clarke, Sailstad, Saltzman and Maayani (1994) Mol. Pharmacol. 46, 477-484]. Our previous studies using CHO-A1 cells have revealed that both the adenosine A1 and 5-HT1B receptor are negatively coupled to adenylyl cyclase activity and stimulate increases in [Ca2+]i, through a pertussis toxin-sensitive pathway. In the present study the selective adenosine A1 receptor agonist N6-cyclopentyladenosine stimulated a pertussis toxin-sensitive increase in total [3H]inositol phosphate accumulation. The sulphated C-terminal octapeptide of cholecystokinin (CCK-8) stimulated a robust and pertussis toxin-insensitive increase in [3H]inositol phosphate accumulation through the activation of CCKA receptors. Co-stimulation of CHO-A1 cells with N6-cyclopentyladenosine and CCK-8 produced a synergistic increase in [3H]inositol phosphate accumulation. The synergistic interaction between N6-cyclopentyladenosine and CCK-8 was abolished in pertussis toxin-treated cells. Synergy between N6-cyclopentyladenosine and CCK-8 still occurred in the absence of extracellular calcium. The 5-HT1B receptor agonist 5-carboxyamidotryptamine did not stimulate a measurable increase in [3H]inositol phosphate accumulation. Furthermore, 5-carboxyamidotryptamine had no significant effect on CCK-8 mediated [3H]inositol phosphate production. Activation of endogenous P2U receptors (Gq/Gll coupled) with ATP gamma S produced a significant increase in [3H]inositol phosphate accumulation. Co-stimulation of CHO-A1 cells with ATP gamma S and CCK-8 produced additive increases in [3H]inositol phosphate accumulation. These data indicate that CHO-A1 cells may prove a useful model system in which to investigate further the mechanisms underlying the intracellular 'cross-talk' between phospholipase C coupled receptors (Gq/Gll linked) and Gi/Go coupled receptors.
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PMID:Synergistic interactions between human transfected adenosine A1 receptors and endogenous cholecystokinin receptors in CHO cells. 879 Oct 2


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