Abstract
BackgroundLysophosphatidic acid (LPA) is a signalling phospholipid with multiple biological functions, mainly mediated through specific G protein-coupled receptors. Aberrant LPA signalling is being increasingly implicated in the pathology of common human diseases, such as arteriosclerosis and cancer. The lifetime of the signalling pool of LPA is controlled by the equilibrium between synthesizing and degradative enzymatic activity. In the current study, we have characterized these enzymatic pathways in rat brain by pharmacologically manipulating the enzymatic machinery required for LPA degradation.ResultsIn rat brain cryosections, the lifetime of bioactive LPA was found to be controlled by Mg2+-independent, N-ethylmaleimide-insensitive phosphatase activity, attributed to lipid phosphate phosphatases (LPPs). Pharmacological inhibition of this LPP activity amplified LPA1 receptor signalling, as revealed using functional autoradiography. Although two LPP inhibitors, sodium orthovanadate and propranolol, locally amplified receptor responses, they did not affect global brain LPA phosphatase activity (also attributed to Mg2+-independent, N-ethylmaleimide-insensitive phosphatases), as confirmed by Pi determination and by LC/MS/MS. Interestingly, the phosphate analog, aluminium fluoride (AlFx-) not only irreversibly inhibited LPP activity thereby potentiating LPA1 receptor responses, but also totally prevented LPA degradation, however this latter effect was not essential in order to observe AlFx--dependent potentiation of receptor signalling.ConclusionsWe conclude that vanadate- and propranolol-sensitive LPP activity locally guards the signalling pool of LPA whereas the majority of brain LPA phosphatase activity is attributed to LPP-like enzymatic activity which, like LPP activity, is sensitive to AlFx- but resistant to the LPP inhibitors, vanadate and propranolol.
Highlights
Lysophosphatidic acid (LPA) is a signalling phospholipid with multiple biological functions, mainly mediated through specific G protein-coupled receptors
The Lipid phosphate phosphatase (LPP)-mediated degradation of LPA is susceptible to the phosphatase inhibitor sodium orthovanadate (Na3VO4) [35] and to propranolol [20,36], better known as a classical β-adrenoceptor blocking agent e.g. used in the treatment of hypertension
We found that exogenously added autotaxin substrate LPC did not boost tonic LPA1 receptor activity suggesting that tonic LPA1 activity in brain sections is not due to LPA formed as a result of autotaxin activity (See Additional file 5: Autotaxin is not responsible for tonic LPA1 activity)
Summary
Lysophosphatidic acid (LPA) is a signalling phospholipid with multiple biological functions, mainly mediated through specific G protein-coupled receptors. Aberrant LPA signalling is being increasingly implicated in the pathology of common human diseases, such as arteriosclerosis and cancer. Lysophosphatidic acid (LPA, 1- or 2-acyl-sn-glycero-3phosphate) is a signalling phospholipid mediating multiple biological responses, such as cellular proliferation, prevention of apoptosis, and platelet aggregation, and is involved in the development and function of the nervous, cardiovascular, immune, and reproductive systems [1,2]. Aberrant LPA signalling has been claimed to be associated with the pathology of common human diseases, such as arteriosclerosis [3] and cancer [4]. Signalling by LPA is mainly mediated through specific G proteincoupled receptors (GPCRs) [5,6,7]. Other proposed pathways for LPA generation include de novo biosynthesis either from glycerol-3phosphate (GP) by glycerol-3-phosphate acyltransferase or from monoacylglycerol (MAG) by monoacylglycerol kinase [15]
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