| Phospholipases hydrolyse phosphatidylcholine or phosphatidylethanolamine generating lipid second messengers
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| In many hormone systems, although receptor-stimulated hydrolysis of PIP2 is transient and rapidly switched off (desensitized), generation of DAG is sustained. Together with the recent emergence of the multiple isoforms of PKC, some of which do not require Ca2+ or DAG for activation (Table 38.3), these findings led to the discovery of additional receptor-coupled lipid-signaling pathways involving hydrolysis of phosphatidylcholine or phosphatidylethanolamine (Fig. 38.10), which can give rise to DAG and other biologically active lipids (Fig. 38.11) in response to a wide range of growth factors and mitogens. Phosphatidylcholine comprises about 40% of total cellular phospholipids. It can be hydrolyzed by distinct phospholipases, generating a diversity of lipid second messengers, including arachidonic acid (generated by PLA2) as well as different species of DAG (generated by PLC) and phosphatidic acid (generated by PLD). In addition, hormone-stimulated phosphatidylethanolamine-PLD activities have also been reported.
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| Figure 38.10 Potential lipid second messengers: phosphoglycerides. R1/R2, fatty acid side chains. |
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| Figure 38.11 Products of phosphatidylcholine breakdown. |
| Some hormones or growth factors can stimulate only one or other of these phospholipases, but other ligands can stimulate all these pathways after binding to their specific receptors. There is therefore the potential to generate multiple distinct species of DAG and phosphatidic acid, reflecting
different fatty-acid side chains (Fig. 38.12) of the PIP2 (predominantly stearate/arachidonate) and phosphatidylcholine, and phosphatidylethanolamine substrates. Moreover, DAG species can be further metabolized to produce arachidonic acid via DAG lipase or, alternatively, DAG can be converted to phosphatidic acid via DAG kinase. Likewise, phosphatidic acid can be interconverted to DAG by the action of phosphatidic acid phosphohydrolase.
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| There is growing evidence that all these distinct lipid second messengers have different targets. For example, it has recently been suggested that the saturated/monounsaturated fatty-acid-containing DAGs derived from phosphatidylcholine-specific phospholipase D (PLD) activation are unable to activate PKC isoforms, and that it is only the stearoyl-arachidonyl-phosphatidic acid species that can modulate activity of the GTPase Ras (see Chapter 41). Generation of these diverse, but related, lipid second messengers therefore provides a mechanism for initiating or terminating hormone-specific responses via particular signal transducers, including differential activation of PKC isoforms.
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