PA As A Signalling Lipid
As described above, PLD hydrolyses PC to form PA and choline. Because choline is very abundant in the cell, PLD activity does not significantly affect choline levels; and choline is unlikely to play any role in signaling.
The role of PLD activation in numerous signaling contexts, combined with the lack of a role for choline, suggests that PA is important in signaling. However, PA is rapidly converted to DAG, and DAG is also known to be a signaling molecule. This raises the question as to whether PA has any direct role in signaling or whether it simply acts as a precursor for DAG production. If it is found that PA acts only as a DAG precursor, then one can raise the question as to why cells should produce DAG using two enzymes when they contain the PLC that could produce DAG in a single step.
PA produced by PLD or by DAGK can be distinguished by the addition of ATP. This will show whether the phosphate group is newly derived from the kinase activity or whether it originates from the PC.
Although PA and DAG are interconvertible, they do not act in the same pathways. Stimuli that activate PLD do not activate enzymes downstream of DAG, and vice versa. For example it was shown that addition of PLD to membranes results in the production of -labeled PA and -labeled phosphoinositides. The addition of DAGK inhibitors eliminates the production of -labeled PA but not the PLD-stimulated production of phosphoinositides.
It is possible that, though PA and DAG are interconvertible, separate pools of signaling and non-signaling lipids may be maintained. Studies have suggested that DAG signaling is mediated by polyunsaturated DAG, whereas PLD-derived PA is monounsaturated or saturated. Thus functional saturated/monounsaturated PA can be degraded by hydrolysing it to form non-functional saturated/monounsaturated DAG, whereas functional polyunsaturated DAG can be degraded by converting it into non-functional polyunsaturated PA.
This model suggests that PA and DAG effectors should be able to distinguish lipids with the same headgroups but with differing acyl chains. Although some lipid-binding proteins are able to insert themselves into membranes and could hypothetically recognise the type of acyl chain or the resulting properties of the membrane, many lipid-binding proteins are cytosolic and localise to the membrane by binding only the headgroups of lipids. Perhaps the different acyl chains can affect the angle of the head-group in the membrane. If this is the case, it suggests that a PA-binding domain must not only be able to bind PA specifically but must also be able to identify those head-groups that are at the correct angle. Whatever the mechanism is, such specificity is possible. It is seen in the pig testes DAGK that is specific for polyunsaturated DAG and in two rat hepatocyte LPPs that dephosphorylate different PA species with different activities. Moreover, the stimulation of SK1 activity by PS in vitro was shown to vary greatly depending on whether dioleoyl (C18:1), distearoyl (C18:0), or 1-stearoyl, 2-oleoyl species of PS were used. Thus it seems that, though PA and DAG are interconvertible, the different species of lipid can have different biological activities; and this may enable the two lipids to maintain separate signaling pathways.
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