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)

The opisthotonos (opt) mutation arose spontaneously in a C57BL/Ks-db2J colony and is the only known, naturally occurring allele of opt. This mutant mouse was first identified based on its ataxic and convulsive phenotype. Genetic and molecular data presented here demonstrate that the type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) protein, which serves as an IP3-gated channel to release calcium from intracellular stores, is altered in the opt mutant. A genomic deletion in the IP3R1 gene removes two exons from the IP3R1 mRNA but does not interrupt the translational reading frame. The altered protein is predicted to have lost several modulatory sites and is present at markedly reduced levels in opt homozygotes. Nonetheless, a strong calcium release from intracellular stores can be elicited in cerebellar Purkinje neurons treated with the metabotropic glutamate receptor (mGluR) agonist quisqualate (QA). QA activates Group 1 mGluRs linked to GTP-binding proteins that stimulate phospholipase C and subsequent production of the intracellular messenger IP3, leading to calcium mobilization via the IP3R1 protein. The calcium response in opt homozygotes shows less attenuation to repeated QA application than in control littermates. These data suggest that the convulsions and ataxia observed in opt mice may be caused by the physiological dysregulation of a functional IP3R1 protein.
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PMID:The type 1 inositol 1,4,5-trisphosphate receptor gene is altered in the opisthotonos mouse. 898 86

Activation of phospholipase C (PLC)-mediated signaling pathways in nonexcitable cells causes the release of Ca2+ from intracellular Ca2+ stores and activation of Ca2+ influx across the plasma membrane. Two types of Ca2+ channels, highly Ca2+-selective ICRAC and moderately Ca2+-selective ISOC, support store-operated Ca2+ entry process. In previous patch-clamp experiments with a human carcinoma A431 cell line we described store-operated Imin/ICRACL plasma membrane Ca2+ influx channels. In the present paper we use whole-cell and single-channel recordings to further characterize store-operated Ca2+ influx pathways in A431 cells. We discovered that (a) ICRAC and ISOC are present in A431 cells; (b) ICRAC currents are highly selective for divalent cations and fully activate within 150 s after initiation of Ca2+ store depletion; (c) ISOC currents are moderately selective for divalent cations (PBa/PCs = 14.5) and require at least 300 s for full activation; (d) ICRAC and ISOC currents are activated by PLC-coupled receptor agonists; (e) ISOC currents are supported by Imin/ICRACL channels that display 8.5-10 pS conductance for sodium; (f) ICRAC single channel conductance for sodium is estimated at 0.9 pS by the noise analysis; (g) Imin/ICRACL channels are activated in excised patches by an amino-terminal fragment of InsP3R1 (InsP3R1N); and (h) InsP3 binding to InsP3R1N is necessary for activation of Imin/ICRACL channels. Our findings provide novel information about store-operated Ca2+ influx pathways in A431 cells.
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PMID:The store-operated calcium entry pathways in human carcinoma A431 cells: functional properties and activation mechanisms. 1283 72

In smooth muscle myocytes, agonist-activated release of calcium ions (Ca2+) stored in the sarcoplasmic reticulum (SR) occurs via different but overlapping transduction pathways. Hence, to fully study how SR Ca2+ channels are activated, the simultaneous activation of different Ca2+ signals should be separated. In rat duodenum myocytes, we have previously characterized that acetylcholine (ACh) induces Ca2+ oscillations by binding to its M2 muscarinic receptor and activating the ryanodine receptor subtype 2. Here, we show that ACh simultaneously evokes a Ca2+ signal dependent on activation of inositol 1,4,5-trisphosphate (InsP3) receptor subtype 1. A pharmacologic approach, the use of antisense oligonucleotides directed against InsP3R1, and the expression of a specific biosensor derived from green-fluorescent protein coupled to the pleckstrin homology domain of phospholipase C, suggested that the InsP3R1-dependent Ca2+ signal is transient and due to a transient synthesis of InsP3 via M3 muscarinic receptor. Moreover, we suggest that both M2 and M3 signalling pathways are modulating phosphatidylinositol 4,5-bisphosphate and InsP3 concentration, thus describing closely interacting pathways activated by ACh in duodenum myocytes.
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PMID:Acetylcholine evokes an InsP3R1-dependent transient Ca2+ signal in rat duodenum myocytes. 1875 12

Interstitial cells of Cajal associated with the myenteric plexus (ICC-MP) are pacemaker cells of the small intestine, producing the characteristic omnipresent electrical slow waves, which orchestrate peristaltic motor activity and are associated with rhythmic intracellular calcium oscillations. Our objective was to elucidate the origins of the calcium transients. We hypothesized that calcium oscillations in the ICC-MP are primarily regulated by the sarcoplasmic reticulum (SR) calcium release system. With the use of calcium imaging, study of the effect of T-type calcium channel blocker mibefradil revealed that T-type channels did not play a major role in generating the calcium transients. 2-Aminoethoxydiphenyl borate, an inositol 1,4,5 trisphosphate receptor (IP(3)R) inhibitor, and U73122, a phospholipase C inhibitor, both drastically decreased the frequency of calcium oscillations, suggesting a major role of IP(3) and IP(3)-induced calcium release from the SR. Immunohistochemistry proved the expression of IP(3)R type I (IP(3)R-I), but not type II (IP(3)R-II) and type III (IP(3)R-III) in ICC-MP, indicating the involvement of the IP(3)R-I subtype in calcium release from the SR. Cyclopiazonic acid, a SR/endoplasmic reticulum calcium ATPase pump inhibitor, strongly reduced or abolished calcium oscillations. The Na-Ca exchanger (NCX) in reverse mode is likely involved in refilling the SR because the NCX inhibitor KB-R7943 markedly reduced the frequency of calcium oscillations. Immunohistochemistry revealed 100% colocalization of NCX and c-Kit in ICC-MP. Testing a mitochondrial NCX inhibitor, we were unable to show an essential role for mitochondria in regulating calcium oscillations in the ICC-MP. In summary, ongoing IP(3) synthesis and IP(3)-induced calcium release from the SR, via the IP(3)R-I, are the major drivers of the calcium transients associated with ICC pacemaker activity. This suggests that a biochemical clock intrinsic to ICC determines the pacemaker frequency, which is likely directly linked to kinetics of the IP(3)-activated SR calcium channel and IP(3) metabolism.
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PMID:On the origin of rhythmic calcium transients in the ICC-MP of the mouse small intestine. 2183 58

Epac, exchange protein directly activated by cAMP, is emerging as a new regulator of cardiac physiopathology. Although its effects are much less known than the classical cAMP effector, PKA, several studies have investigated the cardiac role of Epac, providing evidences that Epac modulates intracellular Ca(2+). In one of the first analyses, it was shown that Epac can increase the frequency of spontaneous Ca(2+) oscillations in cultured rat cardiomyocytes. Later on, in adult cardiomyocytes, it was shown that Epac can induce sarcoplasmic reticulum (SR) Ca(2+) release in a PKA independent manner. The pathway identified involved phospholipase C (PLC) and Ca(2+)/calmodulin kinase II (CaMKII). The latter phosphorylates the ryanodine receptor (RyR), increasing the Ca(2+) spark probability. The RyR, Ca(2+) release channel located in the SR membrane, is a key element in the excitation-contraction coupling. Thus Epac participates in the excitation-contraction coupling. Moreover, by inducing RyR phosphorylation, Epac is arrhythmogenic. A detailed analysis of Ca(2+) mobilization in different microdomains showed that Epac preferently elevated Ca(2+) in the nucleoplasm ([Ca(2+)]n). This effect, besides PLC and CaMKII, required inositol 1,4,5 trisphosphate receptor (IP3R) activation. IP3R is other Ca(2+) release channel located mainly in the perinuclear area in the adult ventricular myocytes, where it has been shown to participate in the excitation-transcription coupling (the process by which Ca(2+) activates transcription). If Epac activation is maintained for some time, the histone deacetylase (HDAC) is translocated out of the nucleus de-repressing the transcription factor myocyte enhancer factor (MEF2). These evidences also pointed to Epac role in activating the excitation-transcription coupling. In fact, it has been shown that Epac induces cardiomyocyte hypertrophy. Epac activation for several hours, even before the cell hypertrophies, induces a profound modulation of the excitation-contraction coupling: increasing the [Ca(2+)]i transient amplitude and cellular contraction. Thus Epac actions are rapid but time and microdomain dependent in the cardiac myocyte. Taken together the results collected indicate that Epac may have an important role in the cardiac response to stress.
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PMID:Epac in cardiac calcium signaling. 2322 Jan 53

Under the guidance and regulation of hormone signaling, large majority of mammalian oocytes go through twice cell cycle arrest-resumption prior to the fertilized egg splits: oocyte maturation and egg activation. Cytosolic free calcium elevations and endoplasmic reticulum calcium store alternations are actively involved in triggering the complex machineries and events during oogenesis. Among these, calcium influx had been implicated in the replenishment of endoplasmic reticulum store during oocyte maturation and calcium oscillation during egg activation. This process also drove successful fertilization and early embryo development. Store-operated Ca2+ entry, acts as the principal force of calcium influx, is composed of STIM1 and Orai1 on the plasma membrane. Besides, transient receptor potential channels also participate in the process of calcium inwards. In this review, we summarize the recent researches on the spatial-temporal distribution of store-operated calcium entry components and transient receptor potential channels. Questions about how these channels play function for calcium influx and what impacts these channels have on oocytes are discussed. At the time of sperm-egg fusion, sperm-specific factor(s) diffuse and enable eggs to mount intracellular calcium oscillations. In this review, we also focus on the basic knowledge and the modes of action of the potential sperm factor phospholipase C zeta, as well as the downstream receptor, type 1 inositol 1,4,5-trisphosphate receptor. From the achievement in the previous several decades, it is easy to find that there are too many doubtful points in the field that need researchers take into consideration and take action in the future.
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PMID:Calcium influx and sperm-evoked calcium responses during oocyte maturation and egg activation. 2917 26