Phosphoinositides diacylglycerol

Phorbol esters are promoters that interact with cellular receptors and activate protein kinase C. Usually protein kinase C is activated by Ca++ and diacylglycerol, both of which result from the hydrolysis of phosphoinositides catalyzed by phospholipase C. Phospholipase C is normally activated by several different growth factors. Thus phorbol esters bypass a tightly regulated step in the control of cell growth. Since protein kinase C phosphorylates various proteins, it is not known how this activity participates in establishing a cancerous line of cells. 

The characteristics of the four major classes of histamine receptors are summarized. Question marks indicate suggestions from the literature that have not been confirmed. AA, arachidonic acid DAG, diacylglycerol Iko,2+, calcium-activated potassium current IP3, inositol 1,4,5-trisphosphate NHE, sodium-proton exchange, PKC, protein kinase C NO, nitric oxide PTPLC, phosphoinositide-specific phospholipase C TXA2, thromboxane A2. Has brain-penetrating characteristics after systemic administration. 

The same basic biochemical control mechanism causes contraction of the smooth muscle as well as secretion of aldosterone. The binding of angiotensin to its receptor activates a membrane phospholipase-C. It catalyses the hydrolysis of phosphoinositide phosphatidylinositol bis-phosphate to produce the two intracellular messengers, inositol trisphosphate (IP3) and diacylglycerol (DAG). 

The Ca2+-phosphoinositide signaling pathway. Key proteins include hormone receptors (R), a G protein (G), a phosphoinositide-specific phospholipase C (PLC), protein kinase C substrates of the kinase (S), calmodulin (CaM), and calmodulin-binding enzymes (E), including kinases, phosphodiesterases, etc. (PIP2, phosphatidylinositol-4,5-bisphosphate DAG, diacylglycerol. Asterisk denotes activated state. Open arrows denote regulatory effects.)... 

As illustrated in Table I, many hormones act by stimulating membrane-bound phospholipases. The most commonly affected enzyme is a phospholipase C with specificity for phosphoinositides, i.e., a phosphoinositidase C (PIC) and, among these, the most relevant has specificity for phosphatidylinositol bisphosphate yielding inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 and DAG act as second messengers to mobilize Ca2+ from intracellular stores and activate the phospholipid- and Ca2+-dependent protein kinase, respectively (protein kinase C) (for reviews see Refs. 87-90). A typical Gp-mediated response of this type occurs in neutrophils exposed to the chemoattractant peptide fMLP [91]. fMLP binds to specific membrane receptors which recognize proteolyzed fragments of bacterial pro-... 

During hormonal stimulation of Ptdlns 4,5-P2 hydrolysis there appears to be a preferential degradation of molecules, such as diacylglycerol and phosphatidic acid, which contain arachidonate in the 2-position. Two separate pathways have been proposed for the release of arachidonic acid from these two products of the phosphoinositide response. The first proposes that diacylglycerol is the source of the liberated arachidonate and that diacylglycerol lipase acts on the DG released by hydrolysis of phosphoinositides. The second suggests that a phosphatidic acid-specific phospholipase A2 is responsible for cleaving the arachidonic acid from phosphati-date. 

The major substrates of All-activated PLC remain a matter of controversy. Purified PLC activated by calcium has been shown to directly hydrolyse PI, PIP and PIP2 in vitro to yield diacylglycerol and, respectively, inositol monophosphate (IPj), inositol bisphosphate (IP2) and inositol trisphosphate (IP3). In intact cells the substrate specificity of receptor-activated PLC has been investigated by monitoring the loss of radiolabeled inositol incorporated into phosphoinositides. In the target tissues under discussion, activation of PLC by All results in an immediate (approx. 15 s) reduction in the levels of PIP2 and PIP and a subsequent loss (approx. 5 min) of PI [26-28]. These losses could result either from the direct PLC-catalysed hy-... 

Fig. 2. Messengers mediating the initial and sustained phases of the All-induced cellular response. Initial phase All-elicited hydrolysis of PIP2 induces a transient rise in cytosolic calcium (via IP3), a transient activation of calcium-, calmodulin-dependent protein kinases, a transient increase in the phosphorylation of early-phase phosphoproteins (Pra-P), and a transient cellular response. Sustained response All-elicited hydrolysis of phosphoinositides generates a sustained increase in the diacylglycerol (DG) content of the plasma membrane. In conjunction with a sustained increase in plasma membrane calcium cycling, DG induces the sustained activation of protein kinase C (CK), the sustained increase in the phosphorylation of late-phase phosphoproteins (P -P) and the sustained cellular response.

I., 2003, Regulation of diacylglycerol kinase alpha by phosphoinositide 3-kinase lipid products. 

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