Regulation of Dopamine Release by CASK-β Modulates Locomotor Initiation in Drosophila melanogaster

Abstract

CASK is an evolutionarily conserved scaffolding protein that has roles in many cell types. In Drosophila, loss of the entire CASK gene or just the CASK- transcript causes a complex set of adult locomotor defects. In this study, we show that the motor initiation component of this phenotype is due to loss of CASK- in dopaminergic neurons and can be specifically rescued by expression of CASK- within this subset of neurons. Functional imaging demonstrates that mutation of CASK- disrupts coupling of neuronal activity to vesicle fusion. Consistent with this, locomotor initiation can be rescued by artificially driving activity in dopaminergic neurons. The molecular mechanism underlying this role of CASK- in dopaminergic neurons involves interaction with Hsc70-4, a molecular chaperone previously shown to regulate calcium-dependent vesicle fusion. These data suggest that there is a novel CASK- -dependent regulatory complex in dopaminergic neurons that serves to link activity and neurotransmitter release.Fil: Slawson, Justin B. Brandeis University; Estados UnidosFil: Kuklin, Elena A. Brandeis University; Estados UnidosFil: Mukherjee, Konark. Brandeis University; Estados UnidosFil: Pírez, Nicolas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Fundación Instituto Leloir; Argentina. Brandeis University; Estados UnidosFil: Donelson, Nathan C. Brandeis University; Estados UnidosFil: Griffith, Leslie C. Brandeis University; Estados Unido