Muskelin Regulates Actin Filament- and Microtubule-Based GABAA Receptor Transport in Neurons

SummaryIntracellular 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 GABAA receptor (GABAAR) trafficking. GABAARs regulate synaptic transmission, plasticity, and network oscillations. GABAAR α1 and muskelin interact directly, undergo neuronal cotransport, and associate with myosin VI or dynein motor complexes in subsequent steps of GABAAR 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.

► Muskelin binds to and undergoes cotransport with the GABAA receptor (GABAAR)
► Muskelin KO mice show altered vesicular transport and altered network oscillations
► Muskelin and GABAARs connect to myosin VI and dynein at different cytoskeletal tracks
► Muskelin is required for both the internalization and degradation of GABAAR