title: Muskelin regulates actin filament- and microtubule-based GABA(A) receptor transport in neurons.
abstract: Intracellular transport regulates protein turnover including endocytosis. Because of the spatial segregation of F-actin and microtubules, internalized cargo vesicles need to employ myosin and dynein motors to traverse both cytoskeletal compartments. Factors specifying cargo delivery across both tracks remain unknown. We identified muskelin to interconnect retrograde F-actin- and microtubule-dependent GABA(A) receptor (GABA(A)R) trafficking. GABA(A)Rs regulate synaptic transmission, plasticity, and network oscillations. GABA(A)R α1 and muskelin interact directly, undergo neuronal cotransport, and associate with myosin VI or dynein motor complexes in subsequent steps of GABA(A)R endocytosis. Inhibition of either transport route selectively interferes with receptor internalization or degradation. Newly generated muskelin KO mice display depletion of both transport steps and a high-frequency ripple oscillation phenotype. A diluted coat color of muskelin KOs further suggests muskelin transport functions beyond neurons. Our data suggest the concept that specific trafficking factors help cargoes to traverse both F-actin and microtubule compartments, thereby regulating their fate.
authors.affiliation: Department of Molecular Neurogenetics, Center for Molecular Neurobiology, ZMNH, University of Hamburg Medical School, Falkenried 94, D-20251 Hamburg, Germany.
authors.forename: Frank F
authors.initials: FF
authors.lastname: Heisler
authors.forename: Sven
authors.initials: S
authors.lastname: Loebrich
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Pechmann
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Maier
authors.forename: Aleksandar R
authors.initials: AR
authors.lastname: Zivkovic
authors.forename: Mariko
authors.initials: M
authors.lastname: Tokito
authors.forename: Torben J
authors.initials: TJ
authors.lastname: Hausrat
authors.forename: Michaela
authors.initials: M
authors.lastname: Schweizer
authors.forename: Robert
authors.initials: R
authors.lastname: Bähring
authors.forename: Erika L F
authors.initials: EL
authors.lastname: Holzbaur
authors.forename: Dietmar
authors.initials: D
authors.lastname: Schmitz
authors.forename: Matthias
authors.initials: M
authors.lastname: Kneussel
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D000818:Animals; D015815:Cell Adhesion Molecules / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008870:Microtubules / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D011963:Receptors, GABA-A / Q000378:metabolism*
chemical_list: D015815:Cell Adhesion Molecules; D047908:Intracellular Signaling Peptides and Proteins; C503020:Mkln1 protein, mouse; D011963:Receptors, GABA-A