Molecular Membrane Neuroscience
Glucose-based lipid biology in nervous systems
A reciprocal relationship existing between glia cells and neurons is vital for brain development and the maintenance of the functional neurons. In 1998, we discovered that the survival and morphological development of hippocampal neurons are completely dependent on the non-essential amino acid, L-seine released actively from astroglia. Non-essential amino acid "L-serine" synthesized from glucose in astroglial is "essential" amino acid for neuron development. Addition of L-serine stimulates the synthesis of neuronal membrane lipids including sphingolipids. We have demonstrated that such metabolic neuron-glial relationship is an essential part to the developing and adult brain in vivo.
In 2006, we were succeeded in determining the complete structure of a new type of glucosylated glycolipid, phosphatidylglucoside (PtdGlc) present in lipid rafts in the murine central nervous system. PtdGlc is composed of saturated fatty acyl chains: C18:0 at the sn-1 and C18:0/C20:0 at the sn-2 positions of the glycerol backbone, donating its presence in lipid rafts. PtdGlc is expressed in the astroglial lineage cells, from radial glia to astroglia, in developing mouse brain. The glycolipid is also detectable in the adult stem cells in brain. Very recently, we successfully identified one of metabolites lyso-PtdGlc produced by radial glia cells as bioactive lipid invoved in chemo-repulsion to developing neurons.
We found that membrane glycoprotein with 7-transmembrane domains “BOSS” is localized in lipid rafts of Drosophila nutrient-sensing tissue, the fat body and brain. BOSS mutant shows elevated circulating glucose and lipid levels, an impaired response to nutrient deprivation (starvation). Since humans/mice have GPRC5s (Gprc5b) that share sequence similarity with BOSS, we provide a new insight of conserved glucose and energy-sensing mechanisms through the membrane glycoproteins in the lipid rafts. In fact, we have shown that Gprc5b knockout mice are protected from high-fat diet-induced obesity and insulin resistant.
Guy AT, Nagatsuka Y, Ooashi N, Inoue M, Nakata A, Greimel P, Inoue A, Nabetani T, Murayama A, Ohta K, Ito Y, Aoki J, Hirabayashi Y*, and Kamiguchi H* (*co-corresponding authors ): "NEURONAL DEVELOPMENT. Glycerophospholipid regulation of modality-specific sensory axon guidance in the spinal cord", Science, 349(6251):974-977, - Research Highlight in Nature Reviews Neuroscience (doi: 10.1038/nrn4035); Recommended in F1000 Prime (Highly Accessed) (2015)
Ishibashi Y, and Hirabayashi Y: "AMP-activated Protein Kinase Suppresses Biosynthesis of Glucosylceramide by Reducing Intracellular Sugar Nucleotides.", J Biol Chem 2015 Jul 17;290(29), 18245-60 (2015)
Kumagai A, Ando R, Miyatake H, Greimel P, Kobayashi T, Hirabayashi Y, Shimogori T, and Miyawaki A. : "Abilirubin-inducible fluorescent protein from eel muscle", Cell, 153(7), 1602-1611 (2013)
Kim YJ, Sano T, Nabetani T, Asano Y, and Hirabayashi Y: "GPRC5B Activates Obesity-Associated Inflammatory Signaling in Adipocytes.", Sci Signal, 5(251) (2012)
Kohyama-Koganeya A, Kim YJ, Miura M, and Hirabayashi Y: "A Drosophila orphan G protein-coupled receptor BOSS functions as a glucose-responding receptor: loss of boss causes abnormal energy metabolism.", Proc Natl Acad Sci U S A, 105(40), 15328-33 (2008)
Nagatsuka Y, Hara-Yokoyama M, Kasama T, Takekoshi M, Maeda F, Ihara S, Fujiwara S, Ohshima E, Ishii K, Kobayashi T, Shimizu K, and Hirabayashi Y: "Carbohydrate-dependent signaling from the phosphatidylglucoside-based microdomain induces granulocytic differentiation of HL60 cells.", Proc Natl Acad Sci U S A, 100, 7454-7459 (2003)
Furuya S, Tabata T, Mitoma J, Yamada K, Yamasaki M, Makino A, Yamamoto T, Watanabe M, Kano M, and Hirabayashi Y.: "L-serine and glycine serve as major astroglia-derived trophic factors for cerebellar Purkinje neurons.", Proc Natl Acad Sci U S A, 97, 11528-11533 (2000)
Kanamori A, Nakayama J, Fukuda MN, Stallcup WB, Sasaki K, Fukuda M, and Hirabayashi Y.: "Expression cloning and characterization of a cDNA encoding a novel membrane protein required for the formation of O-acetylated ganglioside: a putative acetyl-CoA transporter", Proc Natl Acad Sci U S A, 94, 2897-2902 (1997)
Ichikawa S, Sakiyama H, Suzuki G, Hidari KI, and Hirabayashi Y.: "Expression cloning of a cDNA for human ceramide glucosyltransferase that catalyzes the first glycosylation step of glycosphingolipid synthesis", Proc Natl Acad Sci U S A, 93, 4638-4643 (1996)
Ichikawa S, Nakajo N, Sakiyama H, and Hirabayashi Y.: "A mouse B16 melanoma mutant deficient in glycolipids", Proc Natl Acad Sci U S A , 91, 2703-2707 (1994)