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Abstract
ABSTRACTMany membrane receptors activate phospholipase C (PLC) during signalling, triggering changes in the levels of several plasma membrane lipids including phosphatidylinositol (PtdIns), phosphatidic acid (PtdOH) and phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2]. It is widely believed that exchange of lipids between the plasma membrane and endoplasmic reticulum (ER) is required to restore lipid homeostasis during PLC signalling, yet the mechanism remains unresolved. RDGBα (hereafter RDGB) is a multi-domain protein with a PtdIns transfer protein (PITP) domain (RDGB-PITPd). We find that, in vitro, the RDGB-PITPd binds and transfers both PtdOH and PtdIns. In Drosophila photoreceptors, which experience high rates of PLC activity, RDGB function is essential for phototransduction. We show that binding of PtdIns to RDGB-PITPd is essential for normal phototransduction; however, this property is insufficient to explain the in vivo function because another Drosophila PITP (encoded by vib) that also binds PtdIns cannot rescue the phenotypes of RDGB deletion. In RDGB mutants, PtdIns(4,5)P2 resynthesis at the plasma membrane following PLC activation is delayed and PtdOH levels elevate. Thus RDGB couples the turnover of both PtdIns and PtdOH, key lipid intermediates during G-protein-coupled PtdIns(4,5)P2 turnover.
Highlights
Eukaryotic cells are composed of membrane bound subcellular compartments each of which has a unique protein and lipid composition that is central to its function
This degeneration could be rescued by expression of either the full-length wild-type rdgB transgene or the PtdIns transfer protein (PITP) domain of rdgB (Fig. 2A,B)
Given that we found that PtdIns binding was essential for RDGB function in vivo, we hypothesised that if this biochemical property was the only determinant of RDGB function, expression of another PITP should rescue rdgB phenotypes
Summary
Eukaryotic cells are composed of membrane bound subcellular compartments each of which has a unique protein and lipid composition that is central to its function. When cells respond to external stimuli, the chemical identity of the plasma membrane is altered. Cell surface receptors that transduce ligand binding by activating phospholipase C (PLC) enzymes exemplify this problem. Many clinically important receptors including receptor tyrosine kinases (e.g. EGFR, T-cell receptor) and Gprotein-coupled receptors (GPCRs; e.g. muscarinic acetylcholine, metabotropic glutamate receptor) utilise PLC-based signalling pathways. Received 24 April 2015; Accepted 13 July 2015 might provide important insights into the biology and treatment of diseases where such receptor signalling is implicated
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