Phosphatidylserine in the brain: metabolism and function

Abstract

Phosphatidylserine (PS) is the major anionic phospholipid class particularly enriched in the inner leaflet of the plasma membrane in neural tissues. PS is synthesized from phosphatidylcholine or phosphatidylethanolamine by exchanging the base head group with serine, and this reaction is catalyzed by phosphatidylserine synthase 1 and phosphatidylserine synthase 2 located in the endoplasmic reticulum. Activation of Akt, Raf-1 and protein kinase C signaling, which supports neuronal survival and differentiation, requires interaction of these proteins with PS localized in the cytoplasmic leaflet of the plasma membrane. Furthermore, neurotransmitter release by exocytosis and a number of synaptic receptors and proteins are modulated by PS present in the neuronal membranes. Brain is highly enriched with docosahexaenoic acid (DHA), and brain PS has a high DHA content. By promoting PS synthesis, DHA can uniquely expand the PS pool in neuronal membranes and thereby influence PS-dependent signaling and protein function. Ethanol decreases DHA-promoted PS synthesis and accumulation in neurons, which may contribute to the deleterious effects of ethanol intake. Improvement of some memory functions has been observed in cognitively impaired subjects as a result of PS supplementation, but the mechanism is unclear.

Keywords: Cognition; Docosahexaenoic acid; Membranes; Neuron; Serine; Signal transduction.

Fig. 1

Activation of neuronal signaling pathways facilitated by PS. Activation of Akt, protein kinase C and Raf-1 requires translocation from the cytosol to the cytoplasmic surface of the plasma membrane. Translocation is initiated by specific stimuli, for example, growth factor-dependent PIP₃ generation from PIP₂ by PI3 kinase in the case of Akt. Binding to the membrane occurs in part through an interaction of these proteins with PS present in anionic domains of the lipid bilayer, activating the signaling pathways leading to neuronal differentiation and survival. DHA facilitates this mechanism by increasing PS production in neurons, while ethanol has the opposite effect because it inhibits the DHA-induced increase in PS production. R: receptor

Fig. 2

PS synthesis and metabolism in the brain. PS is synthesized by replacement of the choline group of PC by serine in a reaction catalyzed by PSS1, and also by replacement of the ethanolamine group of PE by serine in a reaction catalyzed by PSS2. These synthetic reactions occur in the endoplasmic reticulum. PS is decarboxylated to PE in the mitochondria by PS decarboxylase (PSD). The phosphatidylethanolamine methyltransferase (PEMT) reaction that utilizes S-adenosylmethionine (SAM) to convert PE to PC is indicated as a dashed arrow because more recent findings have demonstrated that previously reported methylation activity in the brain [32,33] is quantitatively insignificant [35,36].

Fig. 3

Pathways for providing serine to the brain. Serine can be taken up from the plasma or synthesized from glucose. The synthesis from glucose occurs in astrocytes where part of the 3-phosphoglycerate produced by glycolysis is converted to serine. The serine is transported out of the astrocytes by the Na⁺-dependent ASCT1 transporter. Serine derived from the astrocytes or plasma is taken up by the neurons through the Na⁺-dependent Asc1 transporter. The neurons utilize part of the incorporated serine for PS production catalyzed by either the PSS1 or PSS2 reactions.

Fig. 4

Intracellular transport of PS. PS synthesized in the endoplasmic reticulum is either transferred to the mitochondria or to transport vesicles for delivery to the Golgi. The PS is then transported from the Golgi to the plasma membrane where it localizes exclusively in the cytoplasmic leaflet of the lipid bilayer and is maintained there by the action of P4-ATPases, a group of ATP-dependent aminophospholipid transferases. Excess PS is removed from the plasma membrane by endocytosis, and it is either recycled to the membrane or delivered to lysosome where it is degraded.

Fig. 5

Detection of 18:0, 22:6-PS by isotope dilution mass spectrometry coupled with high performance liquid chromatography. Ion chromatograms reconstructed for [M-H]⁻ (A) and tandem MS spectrum (B) demonstrates detection of 18:0, 22:6-PS in the plasma membrane. Quantitation is based on d₃₅-18:0, 22:6-PS spiked into the biological samples as an internal standard. Extracted ion chromatograms for m/z 868.74 and 834.53 represents 18:0, 22:6- and d₃₅-18:0, 22:6-PS, respectively. The fragments detected in the MS/MS spectrum indicate that the PS species contains 18:0 and 22:6 fatty acyl chains. Inset: the structure of 18:0, 22:6-PS and fragmentation in MS/MS.

Fig. 6

Hypothetical biosynthetic pathways involved in the formation of N-acylserine. This figure shows the likely mechanism for the synthesis of N-acylphosphatidylserine from PS which involves the transfer of the sn-1 fatty acyl residue from PC to the serine residue of PS mediated by a N-acyltransferase [116], and three potential pathways for the production of N-acylserine from N-acylphosphatidylserine; hydrolysis by phospholipase D (PLD) [116], hydrolysis by phospholipase C (PLC) followed by removal of the phosphate residue of N-acylserine phosphate by the PTPN22 phosphatase [123], or a double O-dacylation of N-acylphosphatidylserine by α,β-hydrolase ABH4 followed by glycerol-phosphodiesterase (PDE)-1-mediated hydrolysis [124].

Fig. 7

Schematic presentation of the specific interaction between anionic PS and basic residues in Akt and PDK1. The basic residues R466/K467 and R15/K20 that bind to PS (red circles) are located near the PIP₃ binding pocket in PDK1 and Akt, respectively. K419 and K420 are located in the regulatory domain of Akt.

Fig. 8

Molecular mechanism of PS involvement in Akt activation. Akt is recruited to the plasma membrane initially by the specific binding of the pleckstrin homology domain (PH) to PIP₃ which is generated by growth factor receptor stimulation. The membrane translocation is secured by the electrostatic interaction of membrane PS with specific PS-binding residues in the Akt pleckstrin homology and regulatory (RD) domains. The Akt interaction with PIP₃ and PS causes Akt interdomain conformational changes that expose T³⁰⁸ and S⁴⁷³ for phosphorylation and activation by PDK1 and mTORC2 kinases, respectively. PDK1 co-localizes with Akt at the plasma membrane through the interaction with not only PIP₃ but also PS. After phosphorylation, active Akt is released from the membrane to perform its downstream functions such as regulating cell survival and cell growth. KD: kinase domain.