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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-β 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-β in dopaminergic neurons and can be specifically rescued by expression of CASK-β within this subset of neurons. Functional imaging demonstrates that mutation of CASK-β 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-β 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-β-dependent regulatory complex in dopaminergic neurons that serves to link activity and neurotransmitter release.
Highlights
IntroductionIts neuromodulatory function is highly conserved across species, contributing to complex biological states and behaviors, including locomotion, attention, learning, sleep, and mood (Costa, 2007; Palmiter, 2008)
Dopamine is a biogenic amine present in most nervous systems
It is interesting that these brain regions are not a direct site of action for CASK-β in locomotion, this does not rule out the possibility that CASK-β affects the function of one of these known motor centers indirectly
Summary
Its neuromodulatory function is highly conserved across species, contributing to complex biological states and behaviors, including locomotion, attention, learning, sleep, and mood (Costa, 2007; Palmiter, 2008). Misregulation of dopaminergic signaling can lead to the development of a number of different human pathologies, the most common of which is Parkinson’s Disease, a neurodegenerative condition characterized by the progressive loss of dopaminergic cells within the substantia nigra (Braak and Del Tredici, 2008). Loss of dopaminergic cells has been directly linked to aberrations in motor function, including tremor, rigidity, bradykinesia, and postural instability (Lees et al, 2009). The vast majority of cases are idiopathic and may stem from heightened sensitivity of the dopaminergic system to inflammation and environmental toxins/stressors, possibly in conjunction with unidentified genetic factors (Thomas and Beal, 2007; Surmeier et al, 2010)
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