title: Ganglioside regulation of AMPA receptor trafficking.
abstract: Gangliosides are major cell-surface determinants on all vertebrate neurons. Human congenital disorders of ganglioside biosynthesis invariably result in intellectual disability and are often associated with intractable seizures. To probe the mechanisms of ganglioside functions, affinity-captured ganglioside-binding proteins from rat cerebellar granule neurons were identified by quantitative proteomic mass spectrometry. Of the six proteins that bound selectively to the major brain ganglioside GT1b (GT1b:GM1 > 4; p < 10(-4)), three regulate neurotransmitter receptor trafficking: Thorase (ATPase family AAA domain-containing protein 1), soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein (γ-SNAP), and the transmembrane protein Nicalin. Thorase facilitates endocytosis of GluR2 subunit-containing AMPA-type glutamate receptors (AMPARs) in an ATPase-dependent manner; its deletion in mice results in learning and memory deficits (J. Zhang et al., 2011b). GluR2-containing AMPARs did not bind GT1b, but bound specifically to another ganglioside, GM1. Addition of noncleavable ATP (ATPγS) significantly disrupted ganglioside binding, whereas it enhanced AMPAR association with Thorase, NSF, and Nicalin. Mutant mice lacking GT1b expressed markedly higher brain Thorase, whereas Thorase-null mice expressed higher GT1b. Treatment of cultured hippocampal neurons with sialidase, which cleaves GT1b (and other sialoglycans), resulted in a significant reduction in the size of surface GluR2 puncta. These data support a model in which GM1-bound GluR2-containing AMPARs are functionally segregated from GT1b-bound AMPAR-trafficking complexes. Release of ganglioside binding may enhance GluR2-containing AMPAR association with its trafficking complexes, increasing endocytosis. Disrupting ganglioside biosynthesis may result in reduced synaptic expression of GluR2-contianing AMPARs resulting in intellectual deficits and seizure susceptibility in mice and humans.
authors.affiliation: Department of Pharmacology and Molecular Sciences.
authors.forename: Jillian
authors.initials: J
authors.lastname: Prendergast
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Department of Neurology.
authors.forename: George K E
authors.identifier: http://orcid.org/0000-0002-1506-6139
authors.initials: GK
authors.lastname: Umanah
authors.affiliation: Department of Pharmacology and Molecular Sciences.
authors.forename: Seung-Wan
authors.initials: SW
authors.lastname: Yoo
authors.affiliation: Solomon H. Snyder Department of Neuroscience.
authors.forename: Olof
authors.initials: O
authors.lastname: Lagerlöf
authors.affiliation: Department of Pharmacology and Molecular Sciences.
authors.forename: Mary G
authors.initials: MG
authors.lastname: Motari
authors.affiliation: Mass Spectrometry and Proteomics Facility, Department of Biological Chemistry, and.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Cole
authors.affiliation: Department of Pharmacology and Molecular Sciences, Solomon H. Snyder Department of Neuroscience.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Huganir
authors.affiliation: Department of Pharmacology and Molecular Sciences, Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Department of Neurology, Solomon H. Snyder Department of Neuroscience.
authors.forename: Ted M
authors.initials: TM
authors.lastname: Dawson
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Department of Neurology, Solomon H. Snyder Department of Neuroscience, Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors.forename: Valina L
authors.initials: VL
authors.lastname: Dawson
authors.affiliation: Department of Pharmacology and Molecular Sciences, Solomon H. Snyder Department of Neuroscience, schnaar@jhu.edu.
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Schnaar
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism; D005678:G(M2) Ganglioside / Q000378:metabolism*; D005732:Gangliosides / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism*; D052067:Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins / Q000378:metabolism
chemical_list: D005732:Gangliosides; D018091:Receptors, AMPA; D052067:Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins; D005678:G(M2) Ganglioside; C016481:trisialoganglioside GT1; D000251:Adenosine Triphosphatases; C558645:Atad1 protein, rat; D000074183:ATPases Associated with Diverse Cellular Activities; C104722:glutamate receptor ionotropic, AMPA 2
keywords: AMPA receptor; GluR2; N-ethylmaleimide-sensitive factor; Nicalin; Thorase; ganglioside