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)

Mammals can taste a wide repertoire of chemosensory stimuli. Two unrelated families of receptors (T1Rs and T2Rs) mediate responses to sweet, amino acids, and bitter compounds. Here, we demonstrate that knockouts of TRPM5, a taste TRP ion channel, or PLCbeta2, a phospholipase C selectively expressed in taste tissue, abolish sweet, amino acid, and bitter taste reception, but do not impact sour or salty tastes. Therefore, despite relying on different receptors, sweet, amino acid, and bitter transduction converge on common signaling molecules. Using PLCbeta2 taste-blind animals, we then examined a fundamental question in taste perception: how taste modalities are encoded at the cellular level. Mice engineered to rescue PLCbeta2 function exclusively in bitter-receptor expressing cells respond normally to bitter tastants but do not taste sweet or amino acid stimuli. Thus, bitter is encoded independently of sweet and amino acids, and taste receptor cells are not broadly tuned across these modalities.
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PMID:Coding of sweet, bitter, and umami tastes: different receptor cells sharing similar signaling pathways. 1258 16

The TRPM subfamily of mammalian TRP channels displays unusually diverse activation mechanisms and selectivities. One member of this subfamily, TRPM5, functions in taste receptor cells and has been reported to be activated through G protein-coupled receptors linked to phospholipase C. However, the specific mechanisms regulating TRPM5 have not been described. Here, we demonstrate that TRPM5 is a monovalent-specific cation channel with a 23 pS unitary conductance. TRPM5 does not display constitutive activity. Rather, it is activated by stimulation of a receptor pathway coupled to phospholipase C and by IP(3)-mediated Ca(2+) release. Gating of TRPM5 was dependent on a rise in Ca(2+) because it was fully activated by Ca(2+). Unlike any previously described mammalian TRP channel, TRPM5 displayed voltage modulation and rapid activation and deactivation kinetics upon receptor stimulation. The most closely related protein, the Ca(2+)-activated monovalent-selective cation channel TRPM4b, also showed voltage modulation, although with slower relaxation kinetics than TRPM5. Taken together, the data demonstrate that TRPM5 and TRPM4b represent the first examples of voltage-modulated, Ca(2+)-activated, monovalent cation channels (VCAMs). The voltage modulation and rapid kinetics provide TRPM5 with an excellent set of properties for participating in signaling in taste receptors and other excitable cells.
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PMID:TRPM5 is a voltage-modulated and Ca(2+)-activated monovalent selective cation channel. 1284 17

The transduction of taste is a fundamental process that allows animals to discriminate nutritious from noxious substances. Three taste modalities, bitter, sweet, and amino acid, are mediated by G protein-coupled receptors that signal through a common transduction cascade: activation of phospholipase C beta2, leading to a breakdown of phosphatidylinositol-4,5-bisphosphate (PIP2) into diacylglycerol and inositol 1,4,5-trisphosphate, which causes release of Ca2+ from intracellular stores. The ion channel, TRPM5, is an essential component of this cascade; however, the mechanism by which it is activated is not known. Here we show that heterologously expressed TRPM5 forms a cation channel that is directly activated by micromolar concentrations of intracellular Ca2+ (K1/2 = 21 microM). Sustained exposure to Ca2+ desensitizes TRPM5 channels, but PIP2 reverses desensitization, partially restoring channel activity. Whole-cell TRPM5 currents can be activated by intracellular Ca2+ and show strong outward rectification because of voltage-sensitive gating of the channels. TRPM5 channels are nonselective among monovalent cations and not detectably permeable to divalent cations. We propose that the regulation of TRPM5 by Ca2+ mediates sensory activation in the taste system.
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PMID:Intracellular Ca2+ and the phospholipid PIP2 regulate the taste transduction ion channel TRPM5. 1465 98

The subjective feeling of cold is mediated by the activation of TRPM8 channels in thermoreceptive neurons by cold or by cooling agents such as menthol. Here, we demonstrate a central role for phosphatidylinositol 4,5-bisphosphate (PI(4,5)P(2)) in the activation of recombinant TRPM8 channels by both cold and menthol. Moreover, we show that Ca(2+) influx through these channels activates a Ca(2+)-sensitive phospholipase C and that the subsequent depletion of PI(4,5)P(2) limits channel activity, serving as a unique mechanism for desensitization of TRPM8 channels. Finally, we find that mutation of conserved positive residues in the highly conserved proximal C-terminal TRP domain of TRPM8 and two other family members, TRPM5 and TRPV5, reduces the sensitivity of the channels for PI(4,5)P(2) and increases inhibition by PI(4,5)P(2) depletion. These data suggest that the TRP domain of these channels may serve as a PI(4,5)P(2)-interacting site and that regulation by PI(4,5)P(2) is a common feature of members of the TRP channel family.
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PMID:PI(4,5)P2 regulates the activation and desensitization of TRPM8 channels through the TRP domain. 1585 9

Two voltage-dependent potassium channels, KCNQ1 and KCNH2, are expressed in the taste buds and were identified as strong candidates involved in the repolarization of taste receptor cells expressing phospholipase C-beta2 and TRPM5 (beta2/M5-TRCs). In cell type-specific expression, KCNQ1 was expressed in most taste bud cells, including beta2/M5-TRCs, whereas KCNH2 was expressed in a subset of beta2/M5-TRCs with no correlation with their taste modality, such as sweet or bitter taste reception. Expression of KCNH2 was restricted to young beta2/M5-TRCs. These results suggest that taste bud cells other than beta2/M5-TRCs are depolarized by some stimuli and also that beta2/M5-TRCs have cell age-dependent molecular mechanisms of repolarization.
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PMID:Taste receptor cells express voltage-dependent potassium channels in a cell age-specific manner. 1687 22

The calcium-sensing receptor (CaR) is expressed in epithelial ducts of both normal human breast and breast cancer tissue, as well as in the MCF-7 cell line as assessed by immunohistochemistry and Western blot analysis. However, to date, there are no data regarding the transduction pathways of CaR in breast cancer cells. In this study, we show that a CaR agonist, spermine, and increased extracellular Ca(2+) ([Ca(2+)](o)) sequentially activate two inward currents at -80 mV. The first was highly permeable to Ca(2+) and inhibited by 2-aminophenyl borate (2-APB). In contrast, the second was more sensitive to Na(+) and Li(+) than to Ca(2+) and insensitive to 2-APB. Furthermore, intracellular dialysis with high Mg(2+), flufenamic acid or amiloride perfusion was without any effect on the second current. Both currents were inhibited by La(3+). Calcium imaging recordings showed that both [Ca(2+)](o) and spermine induced an increase in intracellular calcium ([Ca(2+)](i)) and that removal of extracellular Ca(2+) or perfusion of 2-APB caused a decline in [Ca(2+)](i). It is well known that stimulation of CaR by an increase in [Ca(2+)](o) or with spermine is associated with activation of phospholipase C (PLC). Inhibition of PLC reduced the [Ca(2+)](o)-stimulated [Ca(2+)](i) increase. Lastly, reverse-transcriptase polymerase chain reaction showed that MCF-7 cells expressed canonical transient receptor potential (TRPCs) channels. Our results suggest that, in MCF-7 cells, CaR is functionally coupled to Ca(2+)-permeable cationic TRPCs, for which TRPC1 and TRPC6 are the most likely candidates for the highly selective Ca(2+) current. Moreover, the pharmacology of the second Na(+) current excludes the involvement of the more selective Na(+) transient receptor potential melastatin (TRPM4 and TRPM5) and the classical epithelial Na(+ )channels.
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PMID:Calcium-sensing receptor stimulation induces nonselective cation channel activation in breast cancer cells. 1704 82

TRPM5 is a cation channel that it is essential for transduction of bitter, sweet and umami tastes. Signaling of these tastes involves the activation of G protein-coupled receptors that stimulate phospholipase C (PLC) beta2, leading to the breakdown of phosphatidylinositol bisphosphate (PIP2) into diacylglycerol (DAG) and inositol trisphosphate (IP3), and release of Ca2+ from intracellular stores. TRPM5 forms a nonselective cation channel that is directly activated by Ca2+ and it is likely to be the downstream target of this signaling cascade. Therefore, study of TRPM5 promises to provide insight into fundamental mechanisms of taste transduction. This review highlights recent work on the mechanisms of activation of the TRPM5 channel. The mouse TRPM5 gene encodes a protein of 1,158 amino acids that is proposed to have six transmembrane domains and to function as a tetramer. TRPM5 is structurally most closely related to the Ca(2+)-activated channel TRPM4 and it is more distantly related to the cold-activated channel TRPM8. In patch clamp recordings, TRPM5 channels are activated by micromolar concentrations of Ca2+ and are permeable to monovalent but not divalent cations. TRPM5 channel activity is strongly regulated by voltage, phosphoinositides and temperature, and is blocked by acid pH. Study of TRPM4 and TRPM8, which show similar modes of regulation, has yielded insights into possible structural domains of TRPM5. Understanding the structural basis for TRPM5 function will ultimately allow the design of pharmaceuticals to enhance or interfere with taste sensations.
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PMID:TRPM5 and taste transduction. 1721 64

Inositol 1,4,5-trisphosphate receptor (IP3R) is one of the important calcium channels expressed in the endoplasmic reticulum and has been shown to play crucial roles in various physiological phenomena. Type 3 IP3R is expressed in taste cells, but the physiological relevance of this receptor in taste perception in vivo is still unknown. Here, we show that mice lacking IP3R3 show abnormal behavioral and electrophysiological responses to sweet, umami, and bitter substances that trigger G-protein-coupled receptor activation. In contrast, responses to salty and acid tastes are largely normal in the mutant mice. We conclude that IP3R3 is a principal mediator of sweet, bitter, and umami taste perception and would be a missing molecule linking phospholipase C beta2 to TRPM5 activation.
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PMID:Abnormal taste perception in mice lacking the type 3 inositol 1,4,5-trisphosphate receptor. 1792 4

l-Glutamate elicits the umami taste sensation, now recognized as a fifth distinct taste quality. A characteristic feature of umami taste is its potentiation by 5'-ribonucleotides such as guanosine-5'-monophosphate and inosine 5'-monophosphate, which also elicit the umami taste on their own. Recent data suggest that multiple G protein-coupled receptors contribute to umami taste. This review will focus on events downstream of the umami taste receptors. Ligand binding leads to Gbetagamma activation of phospholipase C beta2, which produces the second messengers inositol trisphosphate and diacylglycerol. Inositol trisphosphate binds to the type III inositol trisphosphate receptor, which causes the release of Ca(2+) from intracellular stores and Ca(2+)-dependent activation of a monovalent-selective cation channel, TRPM5. TRPM5 is believed to depolarize taste cells, which leads to the release of ATP, which activates ionotropic purinergic receptors on gustatory afferent nerve fibers. This model is supported by knockout of the relevant signaling effectors as well as physiologic studies of isolated taste cells. Concomitant with the molecular studies, physiologic studies show that l-glutamate elicits increases in intracellular Ca(2+) in isolated taste cells and that the source of the Ca(2+) is release from intracellular stores. Both Galpha gustducin and Galpha transducin are involved in umami signaling, because the knockout of either subunit compromises responses to umami stimuli. Both alpha-gustducin and alpha-transducin activate phosphodiesterases to decrease intracellular cAMP. The target of cAMP in umami transduction is not known, but membrane-permeant analogs of cAMP antagonize electrophysiologic responses to umami stimuli in isolated taste cells, which suggests that cAMP may have a modulatory role in umami signaling.
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PMID:Umami taste transduction mechanisms. 1957 Dec 14

Mammalian sweet, bitter, and umami taste is mediated by a single transduction pathway that includes a phospholipase C (PLC)beta and one cation channel, TRPM5. However, in insects such as the fruit fly, Drosophila melanogaster, it is unclear whether different tastants, such as bitter compounds, are sensed in gustatory receptor neurons (GRNs) through one or multiple ion channels, as the cation channels required in insect GRNs are unknown. Here, we set out to explore additional sensory roles for the Drosophila TRPA1 channel, which was known to function in thermosensation. We found that TRPA1 was expressed in GRNs that respond to aversive compounds. Elimination of TRPA1 had no impact on the responses to nearly all bitter compounds tested, including caffeine, quinine, and strychnine. Rather, we found that TRPA1 was required in a subset of avoidance GRNs for the behavioral and electrophysiological responses to aristolochic acid. TRPA1 did not appear to be activated or inhibited directly by aristolochic acid. We found that elimination of the same PLC that leads to activation of TRPA1 in thermosensory neurons was also required in the TRPA1-expressing GRNs for avoiding aristolochic acid. Given that mammalian TRPA1 is required for responding to noxious chemicals, many of which cause pain and injury, our analysis underscores the evolutionarily conserved role for TRPA1 channels in chemical avoidance.
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PMID:Drosophila TRPA1 channel mediates chemical avoidance in gustatory receptor neurons. 2040 55


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