Hydrolysis of phosphatidyl inositol-bisphosphate (PIP2) by phospholipase C (PLC) produces diacylglycerol (DAG) and inositol triphosphate (IP3). Both are potent second messengers. IP3 diffuses into the cytosol, but as DAG is a hydrophobic lipid it remains within the plasma membrane. IP3 stimulates the release of calcium ions from the smooth endoplasmic reticulum, while DAG activates the conventional and unconventional protein kinase C (PKC) isoforms, facilitating the translocation of PKC from the cytosol to the plasma membrane. The effects of DAG are mimicked by tumor-promoting phorbol esters. DAG is also a precursor for the biosynthesis of prostaglandins, the endocannabinoid 2-arachidonoylglycerol and an activator of a subfamily of TRP-C (Transient Receptor Potential Canonical) cation channels 3, 6, and 7.
Chau LY, Tai HH.; ''Release of arachidonate from diglyceride in human platelets requires the sequential action of a diglyceride lipase and a monoglyceride lipase.''; PubMedEurope PMCScholia
Riccio A, Mattei C, Kelsell RE, Medhurst AD, Calver AR, Randall AD, Davis JB, Benham CD, Pangalos MN.; ''Cloning and functional expression of human short TRP7, a candidate protein for store-operated Ca2+ influx.''; PubMedEurope PMCScholia
Savinainen JR, Saario SM, Laitinen JT.; ''The serine hydrolases MAGL, ABHD6 and ABHD12 as guardians of 2-arachidonoylglycerol signalling through cannabinoid receptors.''; PubMedEurope PMCScholia
Schaap D, de Widt J, van der Wal J, Vandekerckhove J, van Damme J, Gussow D, Ploegh HL, van Blitterswijk WJ, van der Bend RL.; ''Purification, cDNA-cloning and expression of human diacylglycerol kinase.''; PubMedEurope PMCScholia
Hofmann T, Obukhov AG, Schaefer M, Harteneck C, Gudermann T, Schultz G.; ''Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol.''; PubMedEurope PMCScholia
Blankman JL, Simon GM, Cravatt BF.; ''A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol.''; PubMedEurope PMCScholia
Berridge MJ, Lipp P, Bootman MD.; ''The versatility and universality of calcium signalling.''; PubMedEurope PMCScholia
Moriyama T, Urade R, Kito M.; ''Purification and characterization of diacylglycerol lipase from human platelets.''; PubMedEurope PMCScholia
The IP3 receptor (IP3R) is an intracellular calcium release channel that mobilizes Ca2+ from internal stores in the ER to the cytoplasm. Though its activity is stimulated by IP3, the principal activator of the IP3R is Ca2+. This process of calcium-induced calcium release is central to the mechanism of Ca2+ signalling. The effect of cytosolic Ca2+ on IP3R is complex: it can be both stimulatory and inhibitory and can the effect varies between IP3R isoforms. In general, the IP3Rs have a bell-shaped Ca2+ dependence when treated with low concentrations of IP3; low concentrations of Ca2+ (100–300 nM) are stimulatory but above 300 nM, Ca2+ becomes inhibitory and switches the channel off. The stimulatory effect of IP3 is to relieve Ca2+ inhibition of the channel, enabling Ca2+ activation sites to gate it. Functionally the IP3 receptor is believed to be tetrameric, with results indicating that the tetramer is composed of 2 pairs of protein isoforms.
The IP3 receptor (IP3R) is an intracellular calcium release channel that mobilizes Ca2+ from internal stores in the ER to the cytoplasm. Though its activity is stimulated by IP3, the principal activator of the IP3R is Ca2+. This process of calcium-induced calcium release is central to the mechanism of Ca2+ signalling. The effect of cytosolic Ca2+ on IP3R is complex: it can be both stimulatory and inhibitory and can the effect varies between IP3R isoforms. In general, the IP3Rs have a bell-shaped Ca2+ dependence when treated with low concentrations of IP3; low concentrations of Ca2+ (100–300 nM) are stimulatory but above 300 nM, Ca2+ becomes inhibitory and switches the channel off. The stimulatory effect of IP3 is to relieve Ca2+ inhibition of the channel, enabling Ca2+ activation sites to gate it. Functionally the IP3 receptor is believed to be tetrameric, with results indicating that the tetramer is composed of 2 pairs of protein isoforms.
Diacylglycerol lipase (DAGL) hydrolyzes diacylglycerol (DAG) at the sn-1 position, producing 2-monoacylglycerols, including 2-arachidonlyglycerol (2-AG) and free fatty acid. This reaction was first characterised for the release of arachidonate from membrane phospholipids in platelets, but is also involved in the spatial and temporal regulation of endocannabinoid signaling in the brain. DAGL exhibits strong selectivity for diacylglycerols over phospholipids, monoacylglycerols, triacylglycerols and fatty acid amides, and prefers the acyl group at sn-1 position to that at sn-2.
Monoacylglycerol lipase (MAGL) is a key enzyme in the hydrolysis of the endocannabinoid 2-arachidonoylglycerol to arachidonate and glycerol. In adipocytes MAGL and hormone-sensitive lipase (LIPE) hydrolyze intracellular triglyceride stores. MAGL may also complement lipoprotein lipase (LPL) in completing hydrolysis of monoglycerides resulting from degradation of lipoprotein triglycerides.
Diacylglycerol kinases (DGKs) are intracellular lipid kinases that use ATP to phosphorylate diacylglycerol (DAG)., generating phosphatidic acid (PA). This lowers membrane DAG levels, regulating signalling proteins that require DAG for membrane association such as Protein Kinase C. PA is a signalling molecule that regulates Raf-1 and PKC zeta, and a substrate for the resynthesis of phosphatidylinositol.
Activation of the novel Protein Kinase C (nPKC) isoforms (delta, epsilon, eta and theta) requires binding to the membrane lipid diacylglycerol (DAG). nPKC activation is sensitive to DAG concentration.
Calcium and DAG regulated guanine nucleotide exchange factors (CalDAG-GEFs, also called RasGRPs) contain a regulatory C1 diacylglycerol (DAG) -binding domain analogous to the C1 domain found in Protein Kinase C, and a pair of calcium-binding EF-hand domains. All forms show enhanced activity in response to DAG and bind calcium, but the effect of Ca2+ seems to differ between isoforms. CalDAG-GEFI exhibited additive enhancement of Rap1 activation in response to Ca2+ ionophore and phorbol ester (Kawasaki et al. 1998). RasGRP2, an isofom of CalDAG-GEFI with an alternatively spliced N-terminal extension, reported to target it to the plasma membrane, was stimulated by diacylglycerol but inhibited by calcium (Clyde-Smith et al. 2000). CalDAG-GEF II/RasGRP1 was additively stimulated by Ca2+ ionophore and phorbol ester.
CalDAG-GEFI was found to primarily target Rap1A and inhibit Ras-dependent activation of the Erk/MAP kinase cascade (Kawasaki et al. 1998). RasGRP2 selectively activated N- and Ki-Ras, but not Ha-Ras. It also had Rap1A stimulating activity, but less than CalDAG-GEFI. The difference in substrate specificity seen for these isoforms may be due to their different cellular locations, as prolonged exposure to phorbol esters, or growth in serum, resulted in localization of CalDAG-GEFI to the cell membrane and restoration of Ras exchange activity (Clyde-Smith et al. 2000). CalDAG-GEF II/RasGRP1 targeted Ras proteins rather than Rap (Kawasaki et al. 1998, Ebinu et al. 1998).
Mouse platelets that lack CalDAG-GEFI are severely compromised in integrin-dependent aggregation as a consequence of their inability to signal through CalDAG-GEFI to its target, the small GTPase Rap1 (Crittenden et al. 2004)
TRPC3, 6 and 7 are non-selective cation channels that are activated by diacylglycerol (DAG) independently of protein kinase C activation by DAG. By analogy with the structures of voltage-regulated calcium channels, TRPC channels are probably tetramers of TRPC protein; heterotetramers within the 3/6/7 group have been observed.
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Functionally the IP3 receptor is believed to be tetrameric, with results indicating that the tetramer is composed of 2 pairs of protein isoforms.
Functionally the IP3 receptor is believed to be tetrameric, with results indicating that the tetramer is composed of 2 pairs of protein isoforms.
CalDAG-GEFI was found to primarily target Rap1A and inhibit Ras-dependent activation of the Erk/MAP kinase cascade (Kawasaki et al. 1998). RasGRP2 selectively activated N- and Ki-Ras, but not Ha-Ras. It also had Rap1A stimulating activity, but less than CalDAG-GEFI. The difference in substrate specificity seen for these isoforms may be due to their different cellular locations, as prolonged exposure to phorbol esters, or growth in serum, resulted in localization of CalDAG-GEFI to the cell membrane and restoration of Ras exchange activity (Clyde-Smith et al. 2000). CalDAG-GEF II/RasGRP1 targeted Ras proteins rather than Rap (Kawasaki et al. 1998, Ebinu et al. 1998).
Mouse platelets that lack CalDAG-GEFI are severely compromised in integrin-dependent aggregation as a consequence of their inability to signal through CalDAG-GEFI to its target, the small GTPase Rap1 (Crittenden et al. 2004)