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)

Vascular endothelium appears to be a unique organ. It not only responds to numerous hormonal and chemical signals but also senses changes in physical parameters such as shear stress, producing mediators that modulate the responses of numerous cells, including vascular smooth muscle, platelets, and leukocytes. In many cases, the initial response of endothelial cells to these diverse signals involves elevation of cytosolic Ca2+ and activation of Ca(2+)-dependent enzymes, including nitric oxide synthase and phospholipase A2. Both the release of Ca2+ from intracellular stores, most likely the endoplasmic reticulum, and the influx of Ca2+ from the extracellular space contribute to the [Ca2+]i increase. The most important trigger for Ca2+ release is inositol 1,4,5-trisphosphate, which is generated by the action of phospholipase C, a plasmalemmal enzyme activated in many cases by the receptor-G protein cascade. Ca2+ influx appears to be related to the activity of receptor-G protein-enzyme complex and to the degree of fullness of the endoplasmic reticulum but does not involve voltage-gated Ca2+ channels. The magnitude of the Ca2+ influx depends on the electrochemical gradient, which is modulated by the membrane potential, Vm. Under basal conditions, Vm is dominated by a large inward rectifier K+ current. Some stimuli, e.g., acetylcholine, have been shown to hyperpolarize Vm, thus increasing the electrochemical gradient for Ca2+, which appears to be modulated by activation of Ca(2+)-dependent K+ and Cl- currents. However, the lack of potent and specific blockers for many of the described or postulated channels (e.g., nonselective cation channel, Ca(2+)-activated Cl- channel) makes an estimation of their effect on endothelial cell function rather difficult. Possible future directions of research and clinical implications are discussed.
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PMID:Intracellular calcium, currents, and stimulus-response coupling in endothelial cells. 838 Feb 79

Receptor-mediated activation of a G-protein-coupled inwardly rectifying potassium channel (GIRK) is a common mechanism for synaptic modulation in the CNS. However, evidence for metabotropic glutamate receptor (mGluR) activation of GIRK is virtually nonexistent, despite the widespread and overlapping distribution of these proteins. We examined this apparent paradox by coexpressing mGluRs 1a, 2, and 7 with the GIRK subunits Kir3.1 and Kir3.4 in Xenopus oocytes. Functional expression of GIRK was confirmed by coexpression with the D2 dopamine receptor that is known to activate GIRK in neurons. Agonist activation of each of the three mGluRs evoked inward potassium currents in symmetrical KCI solutions. The current amplitudes evoked by mGluR1a, mGluR2, and D2 were comparable, whereas mGluR7 currents were somewhat smaller. mGluR1a-evoked GIRK currents were not blocked in BAPTA-treated oocytes, demonstrating that GIRK activation was distinct from phospholipase C-mediated activation of the endogenous calcium-dependent chloride current (lCaCl). Pertussis toxin (PTX) treatment significantly reduced both the mGluR and D2 receptor-evoked GIRK currents. In oocytes in which mGluR2 and D2 were coexpressed, activation of mGluR2 occluded additional D2 receptor current, indicating that mGluR2 and D2 receptor coupling to GIRK involves a common G-protein. The efficient coupling of mGluRs to GIRK in oocytes suggests either that mGluR activation of GIRK has been overlooked in neurons or possibly that mGluRs are excluded from GIRK-containing microdomains.
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PMID:Metabotropic glutamate receptors activate G-protein-coupled inwardly rectifying potassium channels in Xenopus oocytes. 881 80

Many ion transporters and channels appear to be regulated by ATP-dependent mechanisms when studied in planar bilayers, excised membrane patches, or with whole-cell patch clamp. Protein kinases are obvious candidates to mediate ATP effects, but other mechanisms are also implicated. They include lipid kinases with the generation of phosphatidylinositol phosphates as second messengers, allosteric effects of ATP binding, changes of actin cytoskeleton, and ATP-dependent phospholipases. Phosphatidylinositol-4,5-bisphosphate (PIP2) is a possible membrane-delimited messenger that activates cardiac sodium-calcium exchange, KATP potassium channels, and other inward rectifier potassium channels. Regulation of PIP2 by phospholipase C, lipid phosphatases, and lipid kinases would thus tie surface membrane transport to phosphatidylinositol signaling. Sodium-hydrogen exchange is activated by ATP through a phosphorylation-independent mechanism, whereas ion cotransporters are activated by several protein kinase mechanisms. Ion transport in epithelium may be particularly sensitive to changes of cytoskeleton that are regulated by ATP-dependent cell signaling mechanisms.
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PMID:Cytoplasmic ATP-dependent regulation of ion transporters and channels: mechanisms and messengers. 907 61

The modulation of a constitutively active IRK1-like inwardly rectifying potassium channel, that is endogenously expressed in the RBL-2H3 cell, was studied with the whole-cell patch-clamp technique. Activation of G-proteins by intracellular application of GTP gamma S revealed a dual modulation of the inward rectifier. An initial increase in inward current amplitude was induced by GTP gamma S, followed by a profound inhibition of the current. The stimulation of the inward rectifier by GTP gamma S was abolished by pretreatment with pertussis toxin. The inhibitory phase of the GTP gamma S-induced response was pertussis toxin-insensitive. Stimulation of the m1-muscarinic receptor expressed in the RBL cell after stable transfection, induced an inhibition of the inwardly rectifying currents. Application of protein kinase C activators such as phorbol 12-myristate 13-acetate and phorbol 12,13-dibutyrate, resulted in a strong inhibition of the currents. Application of the cAMP-dependent protein kinase activator 8-bromo cAMP also induced an inhibition of the inward rectifier. It is concluded that the inward rectifier of the RBL-2H3 cell may be inhibited both by activation of protein kinase C and by cAMP-dependent protein kinase. As this type of inward rectifier is widely expressed in the nervous system, these data imply that the channel can be inhibited by receptors that stimulate phospholipase C and/or stimulate adenylyl cyclase, and can be activated by receptors that inhibit adenylyl cyclase activity.
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PMID:Dual modulation of an inwardly rectifying potassium conductance. 914 58

HIKE is a highly conserved sequence motif that selectively occurs in proteins candidate to bind PH domains, e.g., the beta subunit of heterotrimeric G proteins, kinases, ankyrin and kinesin. Thus, the HIKE region has been predicted to be a protein docking site for PH domains. This work evidentiates recent experimental evidence that unambiguously defines the functional role of HIKE in Gbeta as a multiple effector docking site and as a major regulatory region of G protein's function. Indeed, the Gbeta HIKE interacts with the beta-adrenergic receptor kinase, Galpha, Ggamma, adenylyl cyclase 2, phospholipase C beta2, inward rectifier K channels, calcium channel alpha1B, calmodulin, phosducin, ste20. Quite interestingly, HIKE is located in the Gbeta region that faces the cell membrane. Thus, HIKE also interacts with the cell membrane and may dynamically regulate membrane vs effector binding of the Galphabetagamma trimer. These findings fulfill a major prediction of the HIKE model, i.e., that HIKE is a regulatory region for protein-protein interactions. A role of HIKE as a proteic binding site for PH domains is supported by the profound influence of HIKE mutations on the largely PH-mediated binding of beta-ARK to Gbeta.
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PMID:HIKE, a candidate protein binding site for PH domains, is a major regulatory region of Gbeta proteins. 1032 71

Histamine-releasing neurons are located exclusively in the TM of the hypothalamus, from where they project to practically all brain regions, with ventral areas (hypothalamus, basal forebrain, amygdala) receiving a particularly strong innervation. The intrinsic electrophysiological properties of TM neurons (slow spontaneous firing, broad action potentials, deep after hyperpolarisations, etc.) are extremely similar to other aminergic neurons. Their firing rate varies across the sleep-wake cycle, being highest during waking and lowest during rapid-eye movement sleep. In contrast to other aminergic neurons somatodendritic autoreceptors (H3) do not activate an inwardly rectifying potassium channel but instead control firing by inhibiting voltage-dependent calcium channels. Histamine release is enhanced under extreme conditions such as dehydration or hypoglycemia or by a variety of stressors. Histamine activates four types of receptors. H1 receptors are mainly postsynaptically located and are coupled positively to phospholipase C. High densities are found especially in the hypothalamus and other limbic regions. Activation of these receptors causes large depolarisations via blockade of a leak potassium conductance, activation of a non-specific cation channel or activation of a sodium-calcium exchanger. H2 receptors are also mainly postsynaptically located and are coupled positively to adenylyl cyclase. High densities are found in hippocampus, amygdala and basal ganglia. Activation of these receptors also leads to mainly excitatory effects through blockade of calcium-dependent potassium channels and modulation of the hyperpolarisation-activated cation channel. H3 receptors are exclusively presynaptically located and are negatively coupled to adenylyl cyclase. High densities are found in the basal ganglia. These receptors mediated presynaptic inhibition of histamine release and the release of other neurotransmitters, most likely via inhibition of presynaptic calcium channels. Finally, histamine modulates the glutamate NMDA receptor via an action at the polyamine binding site. The central histamine system is involved in many central nervous system functions: arousal; anxiety; activation of the sympathetic nervous system; the stress-related release of hormones from the pituitary and of central aminergic neurotransmitters; antinociception; water retention and suppression of eating. A role for the neuronal histamine system as a danger response system is proposed.
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PMID:The physiology of brain histamine. 1116 99

The trp (transient receptor potential) gene encodes a Ca2+ channel responsible for the major component of the phospholipase C (PLC) mediated light response in Drosophila. In trp mutants, maintained light leads to response decay and temporary total loss of sensitivity (inactivation). Using genetically targeted PIP2-sensitive inward rectifier channels (Kir2.1) as biosensors, we provide evidence that trp decay reflects depletion of PIP2. Two independent mutations in the PIP2 recycling pathway (rdgB and cds) prevented recovery from inactivation. Abolishing Ca2+ influx in wild-type photoreceptors mimicked inactivation, while raising Ca2+ by blocking Na+/Ca2+ exchange prevented inactivation in trp. The results suggest that Ca2+ influx prevents PIP2 depletion by inhibiting PLC activity and facilitating PIP2 recycling. Without this feedback one photon appears sufficient to deplete the phosphoinositide pool of approximately 4 microvilli.
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PMID:Calcium influx via TRP channels is required to maintain PIP2 levels in Drosophila photoreceptors. 1134 36

The multifunctional cytokine, transforming growth factor beta(1) (TGF-beta(1)), exerts complex effects on astrocytes with early signaling events being less well characterized than transcriptional mechanisms. We examined the effect of TGF-beta(1) on the 14-pS Kir2.3 inward rectifier K(+) channel in rat primary cultured reactive astrocytes. Immunofluorescence study showed that cells co-expressed TGF-beta(1) receptors 1 and 2, Kir2.3, and glial fibrillary acidic protein (GFAP). Patch clamp study showed that TGF-beta(1) (0.1-100 ng/ml) caused a rapid (<5 min) depolarization because of dose-dependent down-regulation of Kir2.3 channels, which was mimicked by the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (10-500 nm) and which was inhibited by the PKC inhibitor calphostin C (100 nm), by PKC desensitization produced by 3 h of exposure to phorbol 12-myristate 13-acetate (100 nm), and by the PKC-delta isoform-specific inhibitor rottlerin (50 microm). Immunoblot analysis and confocal imaging showed that TGF-beta(1) caused PKC-delta translocation to membrane, and co-immunoprecipitation experiments showed that TGF-beta(1) enhanced association between Kir2.3 and PKC-delta. Additional electrophysiological experiments showed that Kir2.3 channel down-regulation was blocked by the phospholipase C inhibitors, neomycin (100 microm) and D609 (200 microm). Given the commonality of signaling involving PLC-PKC-delta, we speculate that TGF-beta(1)-evoked depolarization may be an early signaling event related to gene transcription in astrocytes.
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PMID:Transforming growth factor-beta 1 regulates Kir2.3 inward rectifier K+ channels via phospholipase C and protein kinase C-delta in reactive astrocytes from adult rat brain. 1171 46

G proteins interact with effectors at multiple sites and regulate their activity. The functional significance of multiple contact points is not well understood. We previously identified three residues on distinct surfaces of Gbetagamma that are crucial for G protein-coupled inward rectifier K(+) (GIRK) channel activation. Here we show that mutations at these sites, S67K, S98T, and T128F, abolished or reduced direct GIRK current activation in inside-out patches, but, surprisingly, all mutants synergized with sodium in activating K(+) currents. Each of the three Gbeta(1) mutants bound the channel indicating that the defects reflected mainly functional impairments. We tested these mutants for functional interactions with effectors other than K(+) channels. With N-type calcium channels, Gbetagamma wild type and mutants all inhibited basal currents. A depolarizing pre-pulse relieved Gbetagamma inhibition of Ca(2+) currents by the wild type and the S98T and T128F mutants but not the S67K mutant. Both wild type and mutant Gbetagamma subunits activated phospholipase C beta(2) with similar potencies; however, the S67K mutant showed reduced maximal activity. These data establish a pattern where mutations can alter the Gbetagamma regulation of a specific effector function without affecting other Gbetagamma-mediated functions. Moreover, Ser-67 showed this pattern in all three effectors tested, suggesting that this residue participates in a common functional domain on Gbeta(1) that regulates several effectors. These data show that distinct domains within Gbetagamma subserve specific functional roles.
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PMID:Distinct sites on G protein beta gamma subunits regulate different effector functions. 1212 91

G protein-coupled inward rectifier K(+) (GIRK) channels regulate cellular excitability and neurotransmission. The GIRK channels are activated by a number of inhibitory neurotransmitters through the G protein betagamma subunit (G(betagamma)) after activation of G protein-coupled receptors and inhibited by several excitatory neurotransmitters through activation of phospholipase C. If the inhibition is produced by PKC, there should be PKC phosphorylation sites in GIRK channel proteins. To identify the PKC phosphorylation sites, we performed systematic mutagenesis analysis on GIRK4 and GIRK1 subunits expressed in Xenopus oocytes. Our data showed that the heteromeric GIRK1/GIRK4 channels were inhibited by a PKC activator phorbol 12-myristate 13-acetate (PMA) through reduction of single channel open-state probability. Direct application of the catalytic subunit of PKC to excised patches had a similar inhibitory effect. This inhibition was greatly eliminated by mutation of Ser-185 in GIRK1 and Ser-191 in GIRK4 that remained G protein sensitive. The PKC-dependent phosphorylation seems to mediate the channel inhibition by the excitatory neurotransmitter substance P (SP) as specific PKC inhibitors and mutation of these PKC phosphorylation sites abolished the SP-induced inhibition of GIRK1/GIRK4 channels. Thus, these results indicate that the PKC-dependent phosphorylation underscores the inhibition of GIRK channels by SP, and Ser-185 in GIRK1 and Ser-191 in GIRK4 are the PKC phosphorylation sites.
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PMID:Molecular basis for the inhibition of G protein-coupled inward rectifier K(+) channels by protein kinase C. 1473 2


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