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)

Drosophila melanogaster, an insect amenable to convenient molecular and genetic manipulation, has a highly sensitive olfactory system. A number of Drosophila olfactory mutants have been isolated and characterized. The smellblind mutant has a defect affecting a voltage-gated Na+ channel. The norpA mutant, defective in a phospholipase C, has a reduced response to odorants in one type of olfactory organ, providing genetic evidence for use of the inositol-1,4,5-trisphosphate signal transduction pathway in olfaction. Since the norpA gene is also required for phototransduction, this work demonstrates overlap in the molecular genetic basis of vision and olfaction. Interestingly, genetic analysis indicates that some olfactory information flows through a pathway which does not depend on norpA. Some mutants, such as ptg, acj6 and Sco, show odorant specificity, in the sense that some odorant responses are greatly reduced, whereas others are little affected, if at all. Some, but not all, mutations affect both larval and adult olfactory responses. Two tightly-linked Drosophila genes encode homologues of moth pheromone-binding proteins (PBPs). Genetic analysis may help determine whether PBPs facilitate transit of pheromones to or from olfactory receptor neurons. Information from Drosophila could be useful in designing means of controlling mosquitoes. It may also be possible to study olfactory genes, such as those encoding PBPs, from other insects by mutating them, introducing them into Drosophila and analysing their function in vivo.
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PMID:Genetic and molecular studies of olfaction in Drosophila. 889 4

We investigated the expression and coupling to the phospholipase C signal transduction pathway of metabotropic glutamate receptor (mGluR) subtypes by Western blot analysis and agonist-stimulated inositol monophosphate formation in several brain regions of postnatal day 9 (P9) and adult rats. In the cerebral cortex, hippocampus, corpus striatum, olfactory bulb, cerebellum and hypothalamus, the expression level of mGluR5 was greater at P9 than in adulthood. The mGluR5 signal was very low or absent in the adult cerebellum and hypothalamus. The expression of mGluR1a was slightly greater at P9 in the hypothalamus, hippocampus and olfactory bulb, whereas it substantially increased with age in the cerebellum, and did not change in the cerebral cortex and corpus striatum. mGluR1b and -1c were nearly undetectable by Western blot analysis. The expression level of mGluR5, but not that of mGluR1a, was significantly correlated with the extent of phosphoinositide hydrolysis stimulated by mGluR agonists in slices prepared from these brain regions. The mGluR antagonist cyclopropan[b]chromen-1a-carboxylic acid ethylester (CPCCOEt), potently antagonized responses mediated by mGluR1, but much less potently those mediated by mGluR5a in recombinant cells. CPCCOEt, at a concentration which efficiently blocks mGluR1 responses, did not substantially affect the polyphosphoinositide response in hippocampal or cerebellar slices from newborn animals, and antagonized only a minor component of the polyphosphoinositide response in adult hippocampal slices. CPCCOEt, however, prevented the small stimulation of polyphosphoinositide hydrolysis by mGluR agonists in adult cerebellar slices. We conclude that (i) the efficient mGluR-mediated polyphosphoinositide hydrolysis in 9-day-old rats is mediated by mGluR5; (ii) the increased expression of mGluR1 in the adult cerebellum does not substitute for the decline of mGluR5 expression in the ability to mediate polyphosphoinositide hydrolysis; and therefore (iii) mGluR1a might couple less efficiently than mGluR5 to polyphosphoinositide hydrolysis.
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PMID:Expression and coupling to polyphosphoinositide hydrolysis of group I metabotropic glutamate receptors in early postnatal and adult rat brain. 904 64

Amino acid and bile salt odorants are detected by zebrafish with relatively independent odorant receptors, but the transduction cascade(s) subsequently activated by these odorants remains unknown. Electro-olfactogram recording methods were used to determine the effects of two drugs, reported to affect phospholipase C (PLC)/inositol tripohsphate (IP3)-mediated olfactory transduction in other vertebrate species, on amino acid and bile salt-evoked responses. At the appropriate concentrations, either an IP3-gated channel blocker, ruthenium red (0.01-0.1 microM), or a PLC inhibitor, neomycin (50 microM), reduced amino-acid-evoked responses to a significantly greater extent than bile salt-evoked responses. Excised patch recording techniques were used to measure the affects of these drugs on second-messenger-activated currents. Ruthenium red and neomycin are both effective blockers of the olfactory cyclic nucleotide-gated (CNG) current. Both drugs blocked the CNG channel in a voltage-dependent and reversible manner. No IP3-activated currents could be recorded. The differential effects of ruthenium red and neomycin on odor-evoked responses suggest the activation of multiple transduction cascades. The nonspecific actions of these drugs on odor-activated transduction pathways and our inability to record an IP3-activated current do not permit the conclusion that zebrafish, like other fish species, use a PLC/IP3-mediated transduction cascade in the detection of odorants.
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PMID:Drugs affecting phospholipase C-mediated signal transduction block the olfactory cyclic nucleotide-gated current of adult zebrafish. 949

Chemoelectrical signal transduction in olfactory neurons appears to involve intracellular reaction cascades mediated by heterotrimeric GTP-binding proteins. In this study attempts were made to identify the G protein subtype(s) in olfactory cilia that are activated by the primary (odorant) signal. Antibodies directed against the alpha subunits of distinct G protein subtypes interfered specifically with second messenger reponses elicited by defined subsets of odorants; odor-induced cAMP-formation was attenuated by Galphas antibodies, whereas Galphao antibodies blocked odor-induced inositol 1,4, 5-trisphosphate (IP3) formation. Activation-dependent photolabeling of Galpha subunits with [alpha-32P]GTP azidoanilide followed by immunoprecipitation using subtype-specific antibodies enabled identification of particular individual G protein subtypes that were activated upon stimulation of isolated olfactory cilia by chemically distinct odorants. For example odorants that elicited a cAMP response resulted in labeling of a Galphas-like protein, whereas odorants that elicited an IP3 response led to the labeling of a Galphao-like protein. Since odorant-induced IP3 formation was also blocked by Gbeta antibodies, activation of olfactory phospholipase C might be mediated by betagamma subunits of a Go-like G protein. These results indicate that different subsets of odorants selectively trigger distinct reaction cascades and provide evidence for dual transduction pathways in olfactory signaling.
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PMID:Odorants selectively activate distinct G protein subtypes in olfactory cilia. 964 20

Galanin is a 29- or 30-amino acid peptide with wide-ranging effects on hormone release, feeding behavior, smooth muscle contractility, and somatosensory neuronal function. Three distinct galanin receptor (GALR) subtypes, designated GALR1, 2, and 3, have been cloned from the rat. We report here the cloning of the human GALR2 and GALR3 genes, an initial characterization of their pharmacology with respect to radioligand binding and signal transduction pathways, and a profile of their expression in brain and peripheral tissues. Human GALR2 and GALR3 show, respectively, 92 and 89% amino acid sequence identity with their rat homologues. Radioligand binding studies with 125I-galanin show that recombinant human GALR2 binds with high affinity to human galanin (K(D) = 0.3 nM). Human GALR3 binds galanin with less affinity (IC50 of 12 nM for porcine galanin and 75 nM for human galanin). Human GALR2 was shown to couple to phospholipase C and elevation of intracellular calcium levels as assessed by aequorin luminescence in HEK-293 cells and by Xenopus melanophore pigment aggregation and dispersion assays, in contrast to human GALR1 and human GALR3, which signal predominantly through inhibition of adenylate cyclase. GALR2 mRNA shows a wide distribution in the brain (mammillary nuclei, dentate gyrus, cingulate gyrus, and posterior hypothalamic, supraoptic, and arcuate nuclei), and restricted peripheral tissue distribution with highest mRNA levels detected in human small intestine. In comparison, whereas GALR3 mRNA was expressed in many areas of the rat brain, there was abundant expression in the primary olfactory cortex, olfactory tubercle, the islands of Calleja, the hippocampal CA regions of Ammon's horn, and the dentate gyrus. GALR3 mRNA was highly expressed in human testis and was detectable in adrenal gland and pancreas. The genes for human GALR2 and 3 were localized to chromosomes 17q25 and 22q12.2-13.1, respectively.
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PMID:Molecular characterization and expression of cloned human galanin receptors GALR2 and GALR3. 983 21

To gain an understanding of the olfactory signal transduction process, individual chemosensory neurons have been assessed for odor-induced Ca2+ responses and the molecular elements of transduction cascades using Ca2+ imaging technique in combination with single-cell RT-PCR approaches. It has been demonstrated that responsiveness of cells to cyclic AMP or inositol trisphosphate odorants was blocked by specific adenylyl cyclase inhibitors or phospholipase C inhibitors, respectively. Using specific primers in single-cell RT-PCR analysis, olfactory marker protein, two G protein subtypes (G(olf) and G(o)), and adenylyl cyclase (subtype III) and a phospholipase C (phospholipase Cbeta2-related subtype) were identified. For a subpopulation of sensory neurons it was demonstrated that both transduction cascades coexist and are active in the same cell. These data support the notion that two second messenger pathways are active in olfactory sensory neurons and emphasize the concept of dual transduction cascades in olfaction.
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PMID:Functional and molecular characterization of individual olfactory neurons. 983 26

Novel mRNA isoforms for two members of the group III metabotropic glutamate receptors (mGluRs), called mGluR7b and mGluR8b, were identified from rat brain cerebral cortex and hippocampus. In both cases, the alternative splicing is generated by a similar out-of-frame insertion in the carboxyl-terminus that results in the replacement of the last 16 amino acids of mGluR7 and mGluR8 by 23 and 16 different amino acids, respectively. Distribution analysis for mGluR7 and mGluR8 isoforms revealed that the two splice variants are generally coexpressed in the same brain areas. The few exceptions were the olfactory bulb, in which only the mGluR7a form could be detected by reverse transcription-polymerase chain reaction, and the lateral reticular and ambiguous nuclei, which showed only mGluR8a labelling. Despite expression in the same regions, different mRNA abundance for the two variants of each receptor were observed. When transiently coexpressed in HEK 293 cells with the phospholipase C-activating chimeric G alpha qi9-G-protein, the a and b forms for both receptor subtypes showed a similar pharmacological profile. The rank order of potencies for both was: DL-amino-4-phosphonobutyrate > L-serine-O-phosphate > glutamate. However, the agonist potencies were significantly higher for mGluR8a, b compared with mGluR7a,b. In Xenopus oocytes, glutamate evoked currents only with mGluR8 when coexpressed with Kir 3.1 and 3.4. Glutamate-induced currents were antagonized by the group II/III antagonist (RS)-alpha-cyclopropyl-4-phosphonophenylglycine. In conclusion, the two isoforms of each receptor have identical pharmacological profiles when expressed in heterologous systems, despite structural differences in the carboxyl-terminal domains.
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PMID:Cloning and characterization of alternative mRNA forms for the rat metabotropic glutamate receptors mGluR7 and mGluR8. 987 42

A cDNA clone encoding a protein of 1116 amino acids with significant homology to beta-isoforms of phospholipase C was isolated from lobster olfactory organ cDNA libraries and named lobPLCbeta. This cDNA hybridized predominantly to a 9 kb transcript in RNA from olfactory organ, pereiopod, brain, and eye-eyestalk and to several smaller minor transcripts only in eye-eyestalk. An antiserum raised to the C terminus of lobPLCbeta detected immunoreactivity in a single 130 kDa band in olfactory aesthetasc hairs, olfactory organ, pereiopod, dactyl, and brain. In eye-eyestalk this 130 kDa band was abundant, and minor bands of 100, 79, and 57 kDa also were detected. In cross sections of the aesthetasc hairs, immunoreactivity was detected in the outer dendritic segments of the olfactory receptor neurons, the site of olfactory transduction. A complex odorant caused lobPLCbeta immunoreactivity to increase in membrane fractions and decrease in soluble fractions of homogenates of aesthetasc hairs. The odorant also increased the amount of lobPLCbeta in immunoprecipitates of Galphaq and Gbeta from homogenates of aesthetasc hairs. These results support the conclusion that lobPLCbeta mediates olfactory transduction.
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PMID:A lobster phospholipase C-beta that associates with G-proteins in response to odorants. 1036 22

Mammalian rod cyclic nucleotide gated (CNG) channels (i.e., alpha plus beta subunits) are strongly inhibited by phosphatidylinositol 4, 5-bisphosphate (PIP(2)) when they are expressed in Xenopus oocytes and studied in giant membrane patches. Cytoplasmic Mg-ATP inhibits CNG currents similarly, and monoclonal antibodies to PIP(2) reverse the effect and hyperactivate currents. When alpha subunits are expressed alone, PIP(2) inhibition is less strong; olfactory CNG channels are not inhibited. In giant patches from rod outer segments, inhibition by PIP(2) is intermediate. Other anionic lipids (e.g., phosphatidyl serine and phosphatidic acid), a phosphatidylinositol-specific phospholipase C, and full-length diacylglycerol have stimulatory effects. Although ATP also potently inhibits cGMP-activated currents in rod patches, the following findings indicate that ATP is used to transphosphorylate GMP, generated from cGMP, to GTP. First, a phosphodiesterase (PDE) inhibitor, Zaprinast, blocks inhibition by ATP. Second, inhibition can be rapidly reversed by exogenous regulator of G-protein signaling 9, suggesting G-protein activation by ATP. Third, the reversal of ATP effects is greatly slowed when cyclic inosine 5'-monophosphate is used to activate currents, as expected for slow inosine 5' triphosphate hydrolysis by G-proteins. Still, other results remain suggestive of regulatory roles for PIP(2). First, the cGMP concentration producing half-maximal CNG channel activity (K(1/2)) is decreased by PIP(2) antibody in the presence of PDE inhibitors. Second, the activation of PDE activity by several nucleotides, monitored electrophysiologically and biochemically, is reversed by PIP(2) antibody. Third, exogenous PIP(2) can enhance PDE activation by nucleotides.
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PMID:Do phosphatidylinositides modulate vertebrate phototransduction? 1075 30

Immunocytochemistry using antisera specific for the G-protein alpha subunits G(alphai), G(alphaq), and G(alphas) revealed similar patterns of immunoreactivity in the lobster brain. Immunoreactivity was strongest in neuropil, especially the olfactory and accessory lobes, and was characterized by bundles of fine threads leading to dense concentrations of punctate staining in the glomeruli. This may reflect the concentration of G-protein alpha subunits at synapses. The major differences between the antisera were distinct patterns of staining intensity in subregions of glomeruli of the olfactory and accessory lobes. This result is potentially correlated with previous evidence that these subregions are neurochemically distinct. Neuronal cell bodies contained moderate levels of immunoreactivity at the plasma membrane and faint staining in the cytoplasm. The olfactory globular tract was moderately immunoreactive, but other fiber tracts were weakly immunoreactive. Immunoreactivity in the deutocerebral commissure consisted of small oval cell bodies and strands that formed a reticulated pattern, suggestive of glia. Photoaffinity labelling by using an analog of GTP demonstrated that histamine activated G(alphai) in brain homogenates. Further evidence of G-protein activation was obtained by showing that stimulation with a mixture of neuroactive substances increased the amount of phospholipase C-beta associated with membranes, G(alphaq), and G(beta). The lobster brain, especially in its neuropil regions, is richly endowed with neuromodulatory biochemical pathways involving G(alphai), G(alphaq), and G(alphas).
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PMID:Distribution of G-protein alpha subunits and neurotransmitter activation of g(alphai) and g(alphaq) in the brain of the lobster Homarus americanus. 1086 16


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