Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glutamate is the principal excitatory neurotransmitter in the mammalian central nervous system. After release from presynaptic terminals, glutamate binds to both ionotropic and metabotropic receptors to mediate fast, slow, and persistent effects on synaptic transmission and integrity. There are three types of ionotropic glutamate receptors. N-Methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA), and kainate receptors are principally activated by the agonist bearing its name and are permeable to cationic flux; hence, their activation results in membrane depolarization. All ionotropic glutamate receptors are believed to be composed of four distinct subunits, each of which is topologically arranged with three transmembrane-spanning and one pore-lining (hairpin loop) domain. In contrast, metabotropic glutamate receptors are G protein (guanine nucleotide-binding protein) -coupled receptors linked to second-messenger systems. Group I metabotropic glutamate receptors are linked to phospholipase C, which results in phosphoinositide hydrolysis and release of calcium from intracellular stores. Group II and group III metabotropic glutamate receptors are negatively linked to adenylate cyclase, which catalyzes the production of cyclic adenosine monophosphate. Each metabotropic glutamate receptor is composed of seven transmembrane-spanning domains, similar to other members of the superfamily of metabotropic receptors, which includes noradrenergic, muscarinic acetylcholinergic, dopaminergic, serotonergic (except type 3 receptors), and gamma-aminobutyric acid (GABA) type B receptors. This review summarizes the relevant molecular biology and ontogeny of glutamate receptors in the central nervous system and highlights some of the roles that they can play during brain development and in certain disease states.
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PMID:Molecular biology and ontogeny of glutamate receptors in the mammalian central nervous system. 1522 8

Substance P (SP) has been characterized as an excitatory neurotransmitter and/or neuromodulator in the peripheral and central nervous systems. It is involved in mediating various biological functions such as smooth muscle contraction, neuronal excitation, and pain transmission. Although Lieb et al. reported that intravenous infusion of SP into healthy men led to an increase of paradoxical sleep latency and time awake, little is known about the function and target of SP on sleep-wakefulness cycle in the central nervous system. The ventrolateral preoptic area (vLPO) plays an important role in modulation of sleep-wakefulness cycle. The present study investigated the effect of SP on sleep-wakefulness cycle in the vLPO of rats. Slow wave sleep (SWS) was enhanced after SP was microinjected into bilateral vLPO, while SP receptor antagonist, N-acetyl-l-tryptophan 3,5-bis(trifluoromethyl)-benzyl ester, led to the opposite effect. The effect induced by SP was blocked by U73122, a phospholipase C inhibitor. In addition, 3-mercaptopropionic acid, a glutamic acid decarboxylase inhibitor that inhibits gamma-aminobutyric acid (GABA) synthesis and release, blocked the SP-induced sleep-promoting effect in the vLPO. These results indicate that SP has sleep-promoting effect in the vLPO possibly by GABAergic neurons.
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PMID:Substance P promotes sleep in the ventrolateral preoptic area of rats. 1552 48

Hypothalamic target neurons of estrogen include neurosecretory neurons such as gonadotropin-releasing hormone (GnRH) and dopamine neurons, and local circuitry neurons such as proopiomelanocortin (POMC) and gamma-aminobutyric acid (GABA) neurons. These and other hypothalamic neurons are involved in regulating numerous homeostatic functions including reproduction, thermoregulation, stress responses, feeding and motivated behaviors. Using a combination of techniques to examine the molecular mechanisms leading to physiological changes induced by estrogen, we find that both rapid effects and transcriptional changes alter excitability of hypothalamic neurons. We have identified membrane-initiated, rapid signaling pathways through which 17beta-estradiol (E2) alters synaptic responses in these neurons using whole-cell patch recording in hypothalamic slices from ovariectomized female guinea pigs. E2 rapidly uncouples mu-opioid and GABA(B) receptors from G protein-gated inwardly rectifying K+ (GIRK) channels in POMC and dopamine neurons as manifested by a reduction in the potency of mu-opioid and GABA(B) receptor agonists to activate these channels. Inhibitors of phospholipase C, protein kinase C and protein kinase A block the actions of E2, indicative that the E2 receptor is G protein-coupled to activation of this cascade. Taking advantage of an animal model we developed to investigate estrogen's feedback actions on secretion of gonadotropin-releasing hormone (GnRH), we studied the transcriptional changes induced by estrogen using suppression subtractive hybridization (SSH) and microarray analysis. Many of the observed mRNA expression changes include transcripts encoding proteins critical for neurotransmitter release and receptor dynamics. Some of these include gec-1, PI3-kinase p55gamma, rab11a GTPase, synaptobrevin2, synaptogyrin, taxilin, Ca2+-dependent activator protein for secretion (CAPS) and a number of proteins containing pleckstrin homology domains-domains that are involved in plasma membrane targeting of their host protein. In situ hybridization and quantitative film autoradiography analysis on selected transcripts show differential distribution and expression in hypothalamic nuclei. Furthermore, single-cell PCR analysis reveals these genes to be expressed in neurons such as POMC (and GnRH). Whether these expression changes are mediated by the classical or membrane estrogen receptors has yet to be delineated. More detailed investigations of transcript spatial localization within neurons and their temporal expression, i.e., within minutes or hours, will provide more insight regarding how estrogen alters neuronal excitability and synaptic efficacy that ultimately lead to changes in complex behavior.
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PMID:Estrogen modulation of hypothalamic neurons: activation of multiple signaling pathways and gene expression changes. 1586 23

Ligand-gated ion channels are transmembrane proteins that respond to a variety of transmitters, including acetylcholine, gamma-aminobutyric acid (GABA), glycine, and glutamate [1 and 2]. These proteins play key roles in neurotransmission and are typically found in the nervous system and at neuromuscular junctions [3]. Recently, acetylcholine receptor family members also have been found in nonneuronal cells, including macrophages [4], keratinocytes [5], bronchial epithelial cells [5], and endothelial cells of arteries [6]. The function of these channels in nonneuronal cells in mammals remains to be elucidated, though it has been shown that the acetylcholine receptor alpha7 subunit is required for acetylcholine-mediated inhibition of tumor necrosis factor release by activated macrophages [4]. We show that cup-4, a gene required for efficient endocytosis of fluids by C. elegans coelomocytes, encodes a protein that is homologous to ligand-gated ion channels, with the highest degree of similarity to nicotinic acetylcholine receptors. Worms lacking CUP-4 have reduced phosphatidylinositol 4,5-bisphosphate levels at the plasma membrane, suggesting that CUP-4 regulates endocytosis through modulation of phospholipase C activity.
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PMID:Endocytosis function of a ligand-gated ion channel homolog in Caenorhabditis elegans. 1593 76

Activation of group I metabotropic glutamate receptors (mGluRs) elicits persistent ictaform discharges in guinea pig hippocampal slices, providing an in vitro model of epileptogenesis. The induction of these persistent ictaform bursts is prevented by l-cysteine sulfinic acid (CSA), an agonist at phospholipase D (PLD)-coupled mGluRs. Studies described herein examined the role of protein kinase C (PKC) in both the group I mGluR-mediated induction and CSA-mediated suppression of this form of epileptogenesis. Intracellular recordings were performed from CA3 stratum pyramidale and synchronized burst length was monitored. In the presence of 50 microM picrotoxin, a gamma-aminobutyric acid type A antagonist, 250- to 500-ms synchronized bursts were elicited. (S)-3,5-Dihydroxyphenylglycine (DHPG, 50 microM), an agonist at group I mGluRs, increased the burst length to 1-3 s in duration, a change that persisted after agonist washout. This persistent change in burst length was elicited in the presence of 10 microM chelerythrine, a PKC inhibitor, indicating that DHPG-induced epileptogenesis is PKC independent. However, although PLD activation with CSA (100 microM) was highly effective at suppressing group I mGluR-mediated induction of burst prolongation, CSA application in the presence of chelerythrine was no longer effective and resulted in the expression of persistent ictaform bursts. These data suggest that CSA-mediated suppression of group I mGluR-induced epileptogenesis is PKC dependent. We propose that CSA mediates its effect by PLD-driven activation of PKC, which may desensitize the phospholipase C-linked group I mGluRs and thereby prevent group I mGluR-induced epileptogenesis.
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PMID:Contrasting roles of protein kinase C in induction versus suppression of group I mGluR-mediated epileptogenesis in vitro. 1604 42

The PRIP [phospholipase C related, but catalytically inactive protein] family has been isolated as a novel inositol 1,4,5-trisphosphate binding protein with a domain organization similar to phospholipase C-delta but lacking the enzyme activity, comprising PRIP-1 and PRIP-2. The PRIP-1 gene is expressed predominantly in the brain, while PRIP-2 exhibits a relatively ubiquitous expression in rats and mice. We also found that PRIP-1 plays an important role in type A receptor signaling for gamma-aminobutyric acid in the brain. In this study, we investigated PRIP-1 gene structure and the possible mechanisms involved in the expression. The tissue distribution pattern of PRIP gene expression in humans was similar to that in rodents. 5'RACE (rapid amplification of cDNA ends) analysis using PRIP-1 gene specific primers with human brain mRNA revealed the presence of three new exons, indicating that the PRIP-1 gene is organized into 8 exons intervened by 7 introns. Although three transcripts resulting from the alternative splicing of exon 2 and/or 3 were detected, a transcript lacking exons 2 and 3 was predominantly expressed in humans, suggesting that the translation start codon of human PRIP-1 exists in exon 1. To characterize the human PRIP-1 promoter, transient luciferase assay was carried out with luciferase constructs including various lengths of the 5' flanking region of the PRIP-1 gene. The results indicated that the positive regulatory region is located -237 to -108 bp upstream from the transcription start site. Gel shift assay revealed the specific binding of some nuclear proteins to this region, suggesting that the existence of transcription factors contributes to the positive regulation of PRIP-1 gene expression. Mutation analyses revealed that the binding of a transcription factor, MAZ to the regulatory site leads to the promoter activity, indicating that MAZ is involved in the expression regulation of the human PRIP-1 gene.
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PMID:Characterization of the human PRIP-1 gene structure and transcriptional regulation. 1695 28

CCK is a brain-gut peptide that is abundantly distributed in both gastrointestinal tract and mammalian brain. The sulfated octapeptide fragment of cholecystokinin (CCK-8S) has been shown to be involved in numerous physiological functions such as behavior, anxiety, learning/memory processes and neuropathic pain. CCK-8S is one of the strongest endogenous anti-opioid substances and suppresses opioid peptides-mediated 'pre-synaptic inhibition' of gamma-aminobutyric acid (GABA) release. Here we provide evidence that CCK-8S modulates GABA-evoked membrane depolarization in rat dorsal root ganglion (DRG) neurons using intracellular recording technique. Bath application CCK-8S-induced membrane depolarization in most of the rat DRG neurons. The depolarization was blocked by prolumide but not LY225910. Pretreatment with CCK-8S suppressed the GABA-evoked depolarization in a concentration-dependent manner. The CCK-8S inhibition was also time-dependent and reached the peak at about 2 min. The inhibitory effect of CCK-8S was strongly suppressed by pre-incubation of CCK-B receptor antagonist LY225910, phospholipase C inhibitor U73122, protein kinase C inhibitor chelerythrine and calcium chelator BAPTA-AM, respectively. The protein kinase A inhibitor H-89 did not affect CCK-8S effect. The results suggest that CCK-8S inhibits GABA-A receptor function by activation of CCK-B receptor followed by activation of intracellular PLC-Ca(2+)-PKC cascade. Thus, CCK-8S might enhance nociceptive information transmission through inhibition of the "pre-synaptic inhibition" evoked by GABA, which may explain its role in modulation of primary sensory information (especially pain).
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PMID:Modulatory effect of CCK-8S on GABA-induced depolarization from rat dorsal root ganglion. 1705 64

During the development of the rat hippocampus, both gamma-aminobutyric acid (GABA)(B) autoreceptors and brain-derived neurotrophic factor (BDNF) play important roles in the formation of GABAergic synapses as well as in the GABA(A) receptor-mediated transmissions. While a number of studies have reported rapid effects of BDNF on GABA(A) receptor-mediated responses, the interactions between GABA(B) autoreceptors and BDNF are less clear. Using conventional whole-cell patch-clamp recordings, we demonstrated here that BDNF significantly occludes baclofen-induced suppression of GABA(A) receptor-mediated transmissions in each of the preparations including hippocampal slices prepared from P14 rats, hippocampal CA1 pyramidal neurons isolated from P14 and P21 rats, and cultured hippocampal pyramidal neurons. This effect of BDNF was rapid and reversible, and was mediated via the activation of presynaptic TrkB receptor tyrosine kinases, and subsequent activation of phospholipase C and protein kinase C. On the contrary, in hippocampal CA1 pyramidal neurons isolated from P7 rats, BDNF failed to occlude the GABA(B) receptor-mediated inhibition of GABA release. Thus, the ability of BDNF to occlude the GABA(B) receptor-mediated inhibition of GABA release develops between P7 and P14. This demonstrates a novel aspect of the effects of BDNF on inhibitory transmissions in rat hippocampus, which may have some functional roles in the induction of developmental plasticity and/or pathophysiology of epilepsy.
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PMID:BDNF occludes GABA receptor-mediated inhibition of GABA release in rat hippocampal CA1 pyramidal neurons. 1707 39

We co-immunoprecipitated the Ca(2+)-sensing receptor (CaR) and type B gamma-aminobutyric acid receptor (GABA-B-R) from human embryonic kidney (HEK)-293 cells expressing these receptors and from brain lysates where both receptors are present. CaRs extensively co-localized with the two subunits of the GABA-B-R (R1 and R2) in HEK-293 cell membranes and intracellular organelles. Coexpressing CaRs and GABA-B-R1s in HEK-293 cells suppressed the total cellular and cell surface expression of CaRs and inhibited phospholipase C activation in response to high extracellular [Ca(2+)] ([Ca(2+)](e)). In contrast, coexpressing CaRs and GABA-B-R2s enhanced CaR expression and signaling responses to raising [Ca(2+)](e). The latter effects of the GABA-B-R2 on the CaR were blunted by coexpressing the GABA-B-R1. Coexpressing the CaR with GABA-B-R1 or R2 enhanced the total cellular and cell surface expression of the GABA-B-R1 or R2, respectively. Studies with truncated CaRs indicated that the N-terminal extracellular domain of the CaR participated in the interaction of the CaR with the GABA-B-R1 and R2. In cultured mouse hippocampal neurons, CaRs co-localized with the GABA-B-R1 and R2. CaRs and GABA-B-R1s also co-immunoprecipitated from brain lysates. The expression of the CaR was increased in lysates from GABA-B-R1 knock-out mouse brains and in cultured hippocampal neurons with their GABA-B-R1 genes deleted in vitro. Thus, CaRs and GABA-B-R subunits can form heteromeric complexes in cells, and their interactions affect cell surface expression and signaling of CaR, which may contribute to extracellular Ca(2+)-dependent receptor activation in target tissues.
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PMID:Complex formation with the Type B gamma-aminobutyric acid receptor affects the expression and signal transduction of the extracellular calcium-sensing receptor. Studies with HEK-293 cells and neurons. 1759 80

Extracellular calcium-sensing receptors (CaRs) and metabotropic or type B gamma-aminobutyric acid receptors (GABA-B-Rs), two closely related members of family C of the G protein-coupled receptor superfamily, dimerize in the formation of signaling and membrane-anchored receptor complexes. We tested whether CaRs and two GABA-B-R subunits (R1 and R2) are expressed in mouse growth plate chondrocytes (GPCs) by PCR and immunocytochemistry and whether interactions between these receptors influence the expression and function of the CaR and extracellular Ca(2+)-mediated cell differentiation. Both CaRs and the GABA-B-R1 and -R2 were expressed in the same zones of the growth plate and extensively colocalized in intracellular compartments and on the membranes of cultured GPCs. The GABA-B-R1 co-immunoprecipitated with the CaR, confirming a physical interaction between the two receptors in GPCs. In vitro knockout of GABA-B-R1 genes, using a Cre-lox recombination strategy, blunted the ability of high extracellular Ca(2+) concentration to activate phospholipase C and ERK1/2, suppressed cell proliferation, and enhanced apoptosis in cultured GPCs. In GPCs, in which the GABA-B-R1 was acutely knocked down, there was reduced expression of early chondrocyte markers, aggrecan and type II collagen, and increased expression of the late differentiation markers, type X collagen and osteopontin. These results support the idea that physical interactions between CaRs and GABA-B-R1s modulate the growth and differentiation of GPCs, potentially by altering the function of CaRs.
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PMID:Type B gamma-aminobutyric acid receptors modulate the function of the extracellular Ca2+-sensing receptor and cell differentiation in murine growth plate chondrocytes. 1761 48


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