Diacylglycerol, phosphatidic acid, and their metabolic enzymes in synaptic vesicle recycling

Abstract

The synaptic vesicle (SV) cycle includes exocytosis of vesicles loaded with a neurotransmitter such as glutamate, coordinated recovery of SVs by endocytosis, refilling of vesicles, and subsequent release of the refilled vesicles from the presynaptic bouton. SV exocytosis is tightly linked with endocytosis, and variations in the number of vesicles, and/or defects in the refilling of SVs, will affect the amount of neurotransmitter available for release (Sudhof, 2004). There is increasing interest in the roles synaptic vesicle lipids and lipid metabolizing enzymes play in this recycling. Initial emphasis was placed on the role of polyphosphoinositides in SV cycling as outlined in a number of reviews (Lim and Wenk, 2009; Martin, 2012; Puchkov and Haucke, 2013; Rohrbough and Broadie, 2005). Other lipids are now recognized to also play critical roles. For example, PLD1 (Humeau et al., 2001; Rohrbough and Broadie, 2005) and some DGKs (Miller et al., 1999; Nurrish et al., 1999) play roles in neurotransmission which is consistent with the critical roles for phosphatidic acid (PtdOH) and diacylglycerol (DAG) in the regulation of SV exo/endocytosis (Cremona et al., 1999; Exton, 1994; Huttner and Schmidt, 2000; Lim and Wenk, 2009; Puchkov and Haucke, 2013; Rohrbough and Broadie, 2005). PLD generates phosphatidic acid by catalyzing the hydrolysis of phosphatidylcholine (PtdCho) and in some systems this PtdOH is dephosphorylated to generate DAG. In contrast, DGK catalyzes the phosphorylation of DAG thereby converting it into PtdOH. While both enzymes are poised to regulate the levels of DAG and PtdOH, therefore, they both lead to the generation of PtdOH and could have opposite effects on DAG levels. This is particularly important for SV cycling as PtdOH and DAG are both needed for evoked exocytosis (Lim and Wenk, 2009; Puchkov and Haucke, 2013; Rohrbough and Broadie, 2005). Two lipids and their involved metabolic enzymes, two sphingolipids have also been implicated in exocytosis: sphingosine (Camoletto et al., 2009; Chan et al., 2012; Chan and Sieburth, 2012; Darios et al., 2009; Kanno et al., 2010; Rohrbough et al., 2004) and sphingosine-1-phosphate (Chan, Hu, 2012; Chan and Sieburth, 2012; Kanno et al., 2010). Finally a number of reports have focused on the somewhat less well studies roles of sphingolipids and cholesterol in SV cycling. In this report, we review the recent understanding of the roles PLDs, DGKs, and DAG lipases, as well as sphingolipids and cholesterol play in synaptic vesicle cycling.

A Phosphatidic Acid (PA) conveyor system of continuous intracellular transport from cell membrane to nucleus maintains EGF receptor homeostasis

“…PA can be synthesized endogenously in vivo or added exogenously in vitro and is used as the backbone to generate other phospholipids [28]. Metabolic enzymes convert PA into diacylglycerol (DAG) very rapidly, and because DAG is the precursor for so many other lipids, it too is soon metabolized into other membrane lipids [29, 30]. This means that any upregulation in PA production can be matched over time with a corresponding upregulation in LPPs and in DAG-metabolizing enzymes.…”

Phosphatidic acid and neurotransmission

“…There are data, on the other hand, supporting roles for the regulation of PLDs and DGKs in neurons. A recent review outlines some of regulatory roles of these enzymes are outlined in a recent review (Tu-Sekine, Goldschmidt, 2015). …”

“…The observations that PLD and DGK (Davletov and Montecucco, 2010, Humeau, Vitale, 2001, Liu et al, 2005, Rohrbough and Broadie, 2005, Waring et al, 1999)(Almena and Merida, 2011, Kanoh et al, 2002, Merida et al, 2008, van Blitterswijk and Houssa, 2000)) play roles in neurotransmitter release strongly implicate this class of enzymes in modulating the levels of PtdOH in neurons (Cremona, Di, 1999b, Davletov and Montecucco, 2010, Goldschmidt, Tu-Sekine, 2016, Huttner and Schmidt, 2000, Lauwers, Goodchild, 2016, Lim and Wenk, 2009, Puchkov and Haucke, 2013, Rohrbough and Broadie, 2005, Schwarz, Natarajan, 2011, Tu-Sekine, Goldschmidt, 2015, Tu-Sekine and Raben, 2011, Yuan, Liu, 2015). Much has been written about the regulation of PLDs and has been the subject of numerous other reviews (Bruntz et al, 2014, Exton, 2002a, b, Klein, 2005, Lauwers, Goodchild, 2016, Lee, Kang, 1997, Lee et al, 2000, Sarri et al, 1998, Selvy et al, 2011, Vitale et al, 2005, Waring, Drappatz, 1999, Wenk and De Camilli, 2004).…”

“…It is recognized that this is largely accomplished via a coordinated mechanism at the presynaptic bouton referred to as the synaptic vesicle (SV) cycle where exocytosis of neurotransmitter loaded vesicles is followed by a synchronized endocytosis of empty vesicles, which are refilled and subsequently re-released (Falcieri et al, 1992, Royle and Lagnado, 2010, Schweizer and Ryan, 2006, Sudhof, 2004). Many previous studies led to the discovery of an array of proteins responsible for regulating this cycle and it is now recognized that lipids are also important mediators for SV recycling (Ammar et al, 2013, Cremona and De, 2001, Cremona et al, 1999b, Huttner and Schmidt, 2000, Lim and Wenk, 2009, Puchkov and Haucke, 2013, Rohrbough and Broadie, 2005, Tu-Sekine et al, 2015). …”

“…As a result of the research to examine the role of lipid involvement in neurotransmission, it is now clear that phosphoinositides (PtdIns), diacylglycerol (DAG), and phosphatidic acid (PtdOH), play key roles (Davletov and Montecucco, 2010, Lauwers, Goodchild, 2016, Lim and Wenk, 2009, Rohrbough and Broadie, 2005, Schwarz et al, 2011, Tu-Sekine, Goldschmidt, 2015, Tu-Sekine and Raben, 2011, Yuan et al, 2015). Given their popularity, it is understandable that PtdIns(4,5)P 2 and PtdIns(3,4,5)P 3 have received a great deal of attention (see (Cremona et al, 1999a, Davletov and Montecucco, 2010, Di Paolo and De Camilli, 2006, Di Paolo et al, 2004, Lauwers, Goodchild, 2016, Lim and Wenk, 2009, Martin, 2015, Micheva et al, 2001, Puchkov and Haucke, 2013).…”