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)

Rats were treated with dietary lithium for 30 days, followed by assessment of the activity of the receptor-coupled inositol phospholipid second messenger-producing system in three brain regions. The major effect of long-term lithium treatment was a significant reduction of the response to norepinephrine in all three brain regions that were examined: the cerebral cortex, the hippocampus, and the striatum. After long-term lithium treatment, the response to serotonin was reduced in the hippocampus and striatum, but not the cortex, and the carbachol-induced response was only reduced in the striatum. Lithium treatment did not alter the incorporation of [3H]inositol into phospholipids, the in vitro lithium concentration-dependent accumulation of [3H]inositol monophosphate, or the stimulation by NaF of inositol phospholipid hydrolysis. These results indicate that the decreased responses to agonists after long-term lithium treatment are not likely to be due to depletion of inositol phospholipids or to altered activity of myo-inositol-1-phosphatase, phospholipase C, or the guanine nucleotide-binding protein. It is suggested that long-term lithium treatment may alter receptor number or receptor coupling, perhaps by phosphorylation, thereby selectively lowering the agonist-induced generation of second messengers by the inositol phospholipid system.
 ...
PMID:Long-term lithium treatment selectively reduces receptor-coupled inositol phospholipid hydrolysis in rat brain. 253 62

All of the known pathways for metabolizing the phospholipase C (EC 3.1.4.10) products of phosphoinositide metabolism eventually lead to myo-inositol monophosphates and products that are hydrolyzed by myo-inositol 1-phosphatase (EC 3.1.3.25). That enzyme is inhibited by lithium (Ki about 1 mM). In animals treated with LiCl, elevations of myo-inositol 1-phosphate (1-IP) occur in brain that appear to result from endogenous neural activity for they are diminished by the anesthetics halothane and pentobarbital. Lithium is thus a useful tool for assessing endogenous in vivo cerebral phosphoinositide metabolism. The 1-IP elevation is also useful for revealing in vivo central nervous system (CNS) receptor activity that is stimulated by endogenous or exogenous processes such as the effects of centrally acting drugs and of seizures. Stimulation of the CNS in the presence of lithium causes myo-inositol to be sequestered in 1-IP in proportion to the amount of stimulation. Thus if the inositol level falls sufficiently resynthesis of the phosphoinositides may be compromised and receptor response to stimuli may be reduced. Evidence for such an occurrence would support the theory that this is one mechanism by which lithium acts in the therapy of manic illness. We extended our efforts to identify such a lowering of phosphoinositide levels to mice where cerebral metabolism can be halted more rapidly than in rats. However, the only change detected was a small elevation in phosphatidylinositol 4-phosphate. We were successful, however, in causing all of the phosphoinositides to be reduced in rat cerebral cortex by pilocarpine stimulation after lithium treatment, a procedure that causes seizures. The same procedure causes the largest reduction in cortical myo-inositol levels that we have observed, and thus may represent the point where the inositol decrement is sufficient to interfere with resynthesis of the lipids.
 ...
PMID:Effects of lithium on phosphoinositide metabolism in vivo. 301 84

Lithium remains the most widely used long-term treatment for bipolar affective disorder, but the molecular mechanisms underlying its therapeutic efficacy have not been fully elucidated. Two enzymes involved in the phospholipase C signalling system, namely the myo-inositol monophosphatase (IMPase) and the inositol polyphosphate 1-phosphatase (IPPase), have been postulated as targets for the therapeutic action of lithium in manic-depressive illness. Intriguingly, Drosophila mutants lacking IPPase activity display a defect in synaptic transmission, and this alteration could be phenocopied by lithium exposure. We recently demonstrated the presence of several polymorphisms in the IPPase-encoding inositol polyphosphate 1-phosphatase gene (INPP1) cDNA and suggested that polymorphic variants of the human IPPase might be associated with the striking difference in lithium response among bipolar patients. We report the genomic structure and organization of the INPP1 gene on chromosome 2q32. Based on DNA sequencing of the entire genomic region containing INPP1, we found that the gene consists of six exons and spans more than 25 kb. Expression analysis showed that INPP1 is present as a 1.9 kb mRNA transcript in all organs and tissues examined, including the central nervous system. The level of expression varies, with at least a fourfold higher transcript level in testis compared with other tissues with high expression. A highly polymorphic dinucleotide repeat, (CA)18-25, with an observed heterozygosity of 0.86 was detected immediately downstream of the gene. The present sequence information will be used to further investigate the possible role of the INPP1 gene in lithium-treated bipolar illness.
 ...
PMID:Genomic structure and sequence analysis of a human inositol polyphosphate 1-phosphatase gene (INPP1). 1078 Feb 72

For several decades, lithium has been the drug of choice in the long-term treatment of manic-depressive illness, but the molecular mechanism(s) mediating its therapeutic effects remain to be determined. The enzyme myo-inositol monophosphatase (IMPase) in the phospholipase C signaling system is inhibited by lithium at therapeutically relevant concentrations, and is a candidate target of lithium's mood-stabilizing action. Two genes encoding human IMPases have so far been isolated, namely IMPA1 on chromosome 8q21. 13-21.3 and IMPA2 on chromosome 18p11.2. Interestingly, several studies have indicated the presence of a susceptibility locus for bipolar disorder on chromosome 18p11.2. IMPA2 is therefore a candidate for genetic studies on both etiology and lithium treatment of manic-depressive illness. Here we report that the genomic structure of IMPA2 is composed of eight exons, ranging in size from 46 bp to 535 bp. The promoter region contains several Sp1 elements and lacks a TATA-box, features typical for housekeeping genes. By a preliminary polymorphism screening of exons 2-8 in a sample of 23 Norwegian bipolar patients, we have identified nine single nucleotide polymorphisms (SNPs). Seven of the polymorphisms were located in the introns, one was a silent transition in exon 2 (159T>C) and one was a transition in exon 5 (443G>A) resulting in a predicted amino acid substitution (R148Q). Our data show that even in a small sample of bipolar patients, several variants of the IMPA2 gene can be identified. IMPA2 is therefore an intriguing candidate gene for future association studies of manic-depressive illness.
 ...
PMID:A human myo-inositol monophosphatase gene (IMPA2) localized in a putative susceptibility region for bipolar disorder on chromosome 18p11.2: genomic structure and polymorphism screening in manic-depressive patients. 1082 45

In this review, we discuss the role of phosphatidylinositol 3-kinase (PI3K) and Rap 1 in B-cell receptor (BCR) signaling. PI3K produces lipids that recruit pleckstrin homology domain-containing proteins to the plasma membrane. Akt is a kinase that the BCR activates in this manner. Akt phosphorylates several transcription factors as well as proteins that regulate apoptosis and protein synthesis. Akt also regulates glycogen synthase kinase-3, a kinase whose substrates include the nuclear factor of activated T cells (NF-AT)cl and beta-catenin transcriptional activators. In addition to Akt, PI3K-derived lipids also regulate the activity and localization of other targets of BCR signaling. Thus, a key event in BCR signaling is the recruitment of PI3K to the plasma membrane where its substrates are located. This is mediated by binding of the Src homology (SH) 2 domains in PI3K to phosphotyrosine-containing sequences on membrane-associated docking proteins. The docking proteins that the BCR uses to recruit PI3K include CD19, Cbl, Gab1, and perhaps Gab2. We have shown that Gab1 colocalizes PI3K with SH2 domain-containing inositol phosphatase (SHIP) and SHP2, two enzymes that regulate PI3K-dependent signaling. In contrast to PI3K, little is known about the Rap1 GTPase. We showed that the BCR activates Rap1 via phospholipase C-dependent production of diacylglycerol. Since Rap1 is thought to regulate cell adhesion and cell polarity, it may be involved in B-cell migration.
 ...
PMID:Targets of B-cell antigen receptor signaling: the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase-3 signaling pathway and the Rap1 GTPase. 1104 67

A central feature of Salmonella pathogenicity is the bacterium's ability to enter into non-phagocytic cells. Bacterial internalization is the consequence of cellular responses characterized by Cdc42- and Rac-dependent actin cytoskeleton rearrangements. These responses are triggered by the co-ordinated function of bacterial proteins delivered into the host cell by a specialized protein secretion system termed type III. We report here that SopB, a Salmonella inositol polyphosphatase delivered to the host cell by this secretion system, mediates actin cytoskeleton rearrangements and bacterial entry in a Cdc42-dependent manner. SopB exhibits overlapping functions with two other effectors of bacterial entry, the Rho family GTPase exchange factors SopE and SopE2. Thus, Salmonella strains deficient in any one of these proteins can enter into cells at high efficiency, whereas a strain lacking all three effectors is completely defective for entry. Consistent with an important role for inositol phosphate metabolism in Salmonella-induced cellular responses, a catalytically defective mutant of SopB failed to stimulate actin cytoskeleton rearrangements and bacterial entry. Furthermore, bacterial infection of intestinal cells resulted in a marked increase in Ins(1,4,5,6)P4, a consumption of InsP5 and the activation of phospholipase C. In agreement with the in vivo findings, purified SopB specifically dephosphorylated InsP5 to Ins(1,4,5,6)P4 in vitro. Surprisingly, the inositol phosphate fluxes induced by Salmonella were not caused exclusively by SopB. We show that the SopB-independent inositol phosphate fluxes are the consequence of the SopE-dependent activation of an endogenous inositol phosphatase. The ability of Salmonella to stimulate Rho GTPases signalling and inositol phosphate metabolism through alternative mechanisms is an example of the remarkable ability of this bacterial pathogen to manipulate host cellular functions.
 ...
PMID:A Salmonella inositol polyphosphatase acts in conjunction with other bacterial effectors to promote host cell actin cytoskeleton rearrangements and bacterial internalization. 1113 47

Splenic marginal zone (MZ) and follicular mantle (FO) B cells differ in their responses to stimuli in vitro and in vivo. We have previously shown that MZ cells exhibit greater calcium responses after ligation of membrane IgM (mIgM). We have now investigated the molecular mechanism underlying the difference in calcium responses following ligation of mIgM and studied the response to total B cell receptor ligation in these two subsets. We compared key cellular proteins involved in calcium signaling in MZ and FO cells. Tyrosine phosphorylation and activity of phospholipase C-gamma 2 and Syk protein tyrosine kinase were significantly higher in MZ cells than in FO cells after mIgM engagement, providing a likely explanation for our previous findings. Tyrosine phosphorylation of CD22 and expression of Src homology 2-containing inositol phosphatase and Src homology 2-containing protein tyrosine phosphatase-1 were also higher in the MZ cells. Expression and tyrosine phosphorylation of Btk, BLNK, Vav, or phosphatidylinositol 3-kinase were equivalent. In contrast, stimulation with anti-kappa induced equivalent increases in calcium and activation of Syk in the two subsets. These signals were also equivalent in cells from IgM transgenic, J(H) knockout mice, which have equivalent levels of IgM in both subsets. With total spleen B cells, Btk was maximally phosphorylated at a lower concentration of anti-kappa than Syk. Thus, calcium signaling in the subsets of mature B cells reflects the amount of Ig ligated more than the isotype or the subset and this correlates with the relative tyrosine phosphorylation of Syk.
 ...
PMID:Antigen receptor proximal signaling in splenic B-2 cell subsets. 1120 64