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 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

Serotonin (5-HT) is a central neurotransmitter and a neuromodulator. This amine is involved in many physiological functions and pathological disorders. Most of its effects are mediated by specific 5-HT receptors. In the first part of this paper, the present knowledge of 5-HT receptors is reviewed in terms of both pharmacology and molecular biology. In the second part, the functional properties of 5-HT receptors are analyzed and their involvement in pathophysiological processes is discussed. Most 5-HT receptors belong to the G-protein-coupled receptor family (5-HT1, 5-HT2 and 5-HT4 receptors), whereas one is a member of the ligand-gated ion-channel receptor family (5-HT3 receptor). 5-HT1 receptors are characterized by their high affinity for 5-HT and comprise several subclasses. Most are negatively coupled to adenylate cyclase but the 5-HT1C subtype is linked to phospholipase C activation and resembles the 5-HT2 receptor. By contrast, the newly identified 5-HT4 receptor is positively coupled to adenylate cyclase. Most 5-HT receptors have now been cloned, but their physiological roles are not completely understood. Better knowledge of 5-HT receptors has already led to the development of new drugs, such as buspirone, a 5-HT1A partial agonist devoid of benzodiazepine-like properties for the treatment of generalized anxiety. Anxiolytic properties have also been reported for 5-HT2 and 5-HT3 receptor antagonists. A new and potent anti-migrainous drug, sumatriptan, has recently been selected among compounds obtained by research on the 5-HT1D receptor. This key receptor controls the release of monoamines, amino acids and peptides, and new drugs are expected in the near future. The therapeutic potential of 5-HT3 antagonists is impressive, as these compounds have potent antiemetic, promnesic and antipsychotic properties in various animal models. Two such drugs have already been marketed for the prevention of radiation-induced emesis (ondansetron and granisetron) and are more potent than the antidopaminergic drugs. Many other data suggest that 5-HT receptors might be involved in other illnesses. Some drugs are in the development phase but identification of the relevant receptor is often difficult. Furthermore, the lak of specific ligands for some receptors clearly hinders functional correlations.
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PMID:[Central serotonin receptors. Principal fundamental and functional aspects. Therapeutic applications]. 780 Oct 37

In the last few years, molecular biology has led to the cloning and characterization of several 5-HT receptors (serotonin receptors) in vertebrates and in invertebrates. These studies have allowed identification not only of 5-HT receptors already described but also of novel subtypes. The molecular cloning of 13 different mammalian receptor subtypes revealed an unexpected heterogeneity among 5-HT receptors. Except for the 5-HT3 receptors which are ligand-gated ion channel receptors, all the other 5-HT receptors belong to the large family of receptors interacting with G proteins. Based on their amino acid sequence homology and coupling to second messengers these receptors can be divided into distinct families: the 5-HT1 family contains receptors that are negatively coupled to adenylate cyclase: the 5-HT2 family includes receptors that stimulate phospholipase C; the adenylyl cyclase stimulatory receptors are a heterogeneous group including the 5-HT4 receptor which has not yet been cloned, the Drosophila 5-HTdro1 receptor and two mammalian receptors tentatively named 5-HT6 and 5-HT7 receptors. The 5-HT5A and 5-HT5B receptors might constitute a new family of 5-HT receptors whose effectors are unknown. This review focusses on the molecular characteristics of the cloned 5-HT receptors such as their structure, their effector systems and their distribution within the central nervous system. The existence of a large number of receptors with distinct signalling properties and expression patterns might enable a single substance like 5-HT to generate simultaneously a large panel of effects in many brain structures. The availability of the genes encoding these receptors has already allowed a partial characterization of their structure-function relationship and will probably allow in the future a dissection of the contribution of each of these receptor subtypes to physiology and behaviour.
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PMID:5-Hydroxytryptamine receptor subtypes in vertebrates and invertebrates. 789 28

Serotonin neurons in the rostral and caudal brainstem raphe nuclear groups give rise to collateralized ascending and descending projections which provide modulatory input into most networks throughout the entire neuraxis. The rostral raphe system is interconnected with target forebrain areas through reciprocal limbic-midbrain loops, which suggests that serotonin has a role in the regulation of complex intelligent adaptive behavior. Serotonergic pathways sensitize brainstem and spinal cord central rhythmic pattern generators which organize repetitive autonomic and motor activities, e.g. oral-buccal and nutritive behaviors, facilitate tonically active motor neurons innervating antigravity muscles, and disfacilitate somatosensory information processing. Serotonin effects are mediated by multiple receptor subtypes with distinct pre- and postsynaptic localization and regional distribution pattern. They belong to the G protein superfamily, coupling to adenylate cyclase (5-HT1,4,5,6,7) or phospholipase C (5-HT2), and to the ligand-gated ion channel superfamily (5-HT3). Drugs acting at these receptors are known to modulate various aspects of cooperative social behavior and responding latency, i.e. impulsivity, in a variety of experimental models of anxiety and depression. The clinical efficacy of the so-called selective serotonin reuptake inhibitors (SSRIs) in disorders characterized by poor impulse control, e.g. bulimia nervosa, obsessive-compulsive disorder (OCD) and violent suicidal or homicidal behavior, may likewise be due to improved responding latency.
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PMID:Psychopharmacology of central serotonergic systems. 861 4

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 serotonin 5-HT2 receptor stimulation on long-term potentiation (LTP) in the primary visual cortex was investigated by using rat brain slices in vitro. Field potentials evoked by stimulation of layer IV were recorded in layer II/III. The 5-HT2 receptor agonist 1-(2,5-dimethyl-4-iodophenyl)-2-aminopropane (DOI) did not affect baseline synaptic potentials evoked by single-pulse test stimulation, but significantly inhibited the induction of LTP in a concentration-dependent manner (0.1-10 microM). The LTP-inhibiting effect of DOI (10 microM) was blocked by the 5-HT2,7 receptor antagonist ritanserin (10 microM), but not by the 5-HT1A receptor antagonist NAN-190 (10 microM) nor by the 5-HT3,4 receptor antagonist MDL72222 (10 microM). The inhibitory effect of DOI was also blocked by the phospholipase C inhibitor U73122, but not by its inactive analogue U73343. These results suggest that visual cortex LTP is inhibited by activation of the 5-HT2 receptor-phospholipase C system. In addition, the LTP-inhibiting effect of DOI was abolished by the presence of the GABAA receptor antagonist bicuculline (10 microM), suggesting that 5-HT2 receptor-mediated inhibition of visual cortex LTP is dependent on GABAergic inhibition.
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PMID:The serotonin 5-HT2 receptor-phospholipase C system inhibits the induction of long-term potentiation in the rat visual cortex. 1076 67

There are several receptors capable of inducing activating generator potentials in cough-associated afferent terminals in the airways. The chemical receptors leading to generator potentials can be subclassified into ionotropic and metabotropic types. An ionotropic receptor has an agonist-binding domain, and also serves directly as an ion channel that is opened upon binding of the agonist. Examples of ionotropic receptors found in airway sensory nerve terminals include receptors for serotonin (5-HT3 receptors), ATP (P2X receptors), acetylcholine (nicotinic receptors), receptors for capsaicin and related vanilloids (TRPV1 receptors), and acid receptors (acid sensing ion channels). Afferent nerve terminals can also be depolarized via activation of metabotropic or G-protein coupled receptors (GPCRs). Among the GPCRs that can lead to activation of airway afferent fibers include bradykinin B2 and adenosine A1 receptors. The signaling events leading to GPCR-mediated membrane depolarization are more complex than that seen with ionotropic receptors. The GPCR-mediated effects are thought to occur through classical second messenger systems such as activation of phospholipase C. This may lead to membrane depolarization through interaction with specific ionotropic receptors (such as TRPV1) and/or various types of calcium activated channels.
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PMID:Ionotropic and metabotropic receptor mediated airway sensory nerve activation. 1556 76

The striatum is richly innervated by serotonergic afferents from the raphe nucleus. We explored the effects of this input on striatal cholinergic interneurons from rat brain slices, by means of both conventional intracellular and whole-cell patch-clamp recordings. Bath-applied serotonin (5-HT, 3-300 microM), induced a dose-dependent membrane depolarization and increased the rate of spiking. This effect was mimicked by the 5-HT reuptake blockers citalopram and fluvoxamine. In voltage-clamped neurons, 5-HT induced an inward current, whose reversal potential was close to the K(+) equilibrium potential. Accordingly, the involvement of K(+) channels was confirmed either by increasing extracellular K(+) concentration and by blockade of K(+) channels with barium. Single-cell reverse transcriptase-polymerase chain reaction (RT-PCR) profiling demonstrated the presence of 5-HT2C, 5-HT6, and 5-HT7 receptor mRNAs in identified cholinergic interneurons. The depolarization/inward current induced by 5-HT was partially mimicked by the 5-HT2 receptor agonist 2,5-dimethoxy-4-iodoamphetamine and antagonized by both ketanserin and the selective 5-HT2C antagonist RS102221, whereas the selective 5-HT3 and 5-HT4 receptor antagonists tropisetron and RS23597-190 had no effect. The depolarizing response to 5-HT was also reduced by the selective 5-HT6 and 5-HT7 receptor antagonists SB258585 and SB269970, respectively, and mimicked by the 5-HT7 agonist, 5-CT. Accordingly, activation of either 5-HT6 or 5-HT7 receptor induced an inward current. The 5-HT response was attenuated by U73122, blocker of phospholipase C, and by SQ22,536, an inhibitor of adenylyl cyclase. These results suggest that 5-HT released by serotonergic fibers originating in the raphe nuclei has a potent excitatory effect on striatal cholinergic interneurons.
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PMID:Endogenous serotonin excites striatal cholinergic interneurons via the activation of 5-HT 2C, 5-HT6, and 5-HT7 serotonin receptors: implications for extrapyramidal side effects of serotonin reuptake inhibitors. 1720 14