Diacylglycerols signaling

Tolan, D., Conway, A-M., Pyne, N.J. and Pyne, S., 1997, Sphingosine prevents diacylglycerol signaling to mitogen-activated protein kinase in airway smooth muscle. Am. J. Physiol. 273 (Cell. Physiol 42) C928-C936. 

De Koninck P, Schulman H. Sensitivity of CaM kinase 11 to the frequency of Ca + oscillations. Science 1998 279 227-230. Oancea E, Meyer T. Protein kinase C as a molecular machine for decoding calcium and diacylglycerol signals. Cell... 

Toker, A. 2005. The biology and biochemistry of diacylglycerol signalling. Meeting on molecular advances in diacylglycerol signalling. EMBO Rep. 6 310-314. 

Docampo, R., and Pignataro, O. P. (1991) The inositol phosphate/diacylglycerol signalling pathway in Trypanosoma cruzi. Biochem. J. 275 407-411. 

The spatial and steric requirements for high affinity binding to protein kinase C (PKC), a macromolecule that has not yet been crystallized, were determined. Protein kinase C plays a critical role in cellular signal transduction and is in part responsible for cell differentiation. PKC was identified as the macromolecular target for the potent tumor-promoting phorbol esters (25). The natural agonists for PKC are diacylglycerols (DAG) (26). The arrows denote possible sites of interaction. 

Excitation of smooth muscle via alpha-1 receptors (eg, in the utems, vascular smooth muscle) is accompanied by an increase in intraceUular-free calcium, possibly by stimulation of phosphoUpase C which accelerates the breakdown of polyphosphoinositides to form the second messengers inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 releases intracellular calcium, and DAG, by activation of protein kinase C, may also contribute to signal transduction. In addition, it is also thought that alpha-1 adrenergic receptors may be coupled to another second messenger, a pertussis toxin-sensitive G-protein that mediates the translocation of extracellular calcium. 

Signaling by PKC is terminated by concentrations of its ligands dropping to basal levels (i.e., Ca2+ and diacylglycerol) and by dephosphorylation of the three processing sites. Dephosphorylation is controlled, in part, by a recently discovered hydrophobic phosphorylation motif phosphatase. This phosphatase, PHLPP (for PH domain Leucine-rich repeat Protein Phosphatase) dephosphorylates conventional and novel PKC isozymes, initiating their downregulation. 

Figure 1. Simplified schematic of receptor-mediated signal transduction in neutrophils. Binding of ligand to the receptor activates a guanine-nucleotide-binding protein (G protein), which then stimulates phospholipase C. Phosphatidylinositol 4,5-bis-phosphate is cleaved to produce diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). DAG stimulates protein kinase C. IP3 causes the release of Ca from intracellular stores, which results in an increase in the cytosolic Ca concentration. This increase in Ca may stimulate protein kinase C, calmodulin-dependent protein kinases, and phospholipase A2. Protein phosphorylation events are thought to be important in stimulating degranulation and oxidant production. In addition, ionic fluxes occur across the plasma membrane. It is possible that phospholipase A2 and ionic channels may be governed by G protein interactions. ...

The inositol is present in ph osphatidylinositol as the stereoisomer, myoinositol (Figure 14—8). Phosphatidylinositol 4,5-hisphosphate is an important constituent of cell membrane phosphohpids upon stimulation by a suitable hormone agonist, it is cleaved into diacylglycerol and inositol trisphosphate, both of which act as internal signals or second messengers. 

Less explored is the role and metabolic fate of 2-AG. It is possible that in many tissues, 2-AG is only an intermediate of a signaling pathway that generates 1,2-diacylglycerol and arachidonic acid, two well-known signaling molecules. In the brain however, 2-AG may have regulatory roles, since it escapes immediate metabolism and accumulates in response to stimuli-generated Ca2+ surges (Stella, 1997). These differences may arise... 

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