The Conserved MAP Kinase SWIP-13/ERK8 Regulates Dopamine Signaling Through Control of the Presynaptic Dopamine Transporter

Abstract

Dopamine is a critical neurotransmitter used across phylogeny to regulate many aspects of behavior. Synaptic control of dopamine signaling is vital for normal nervous system function in humans, and dysregulation of this signaling is associated with many disease states, including addiction, attention-hyperactivity deficit disorder (ADHD), schizophrenia, and Parkinson’s disease. The model organism Caenorhabditis elegans is a useful system in which to dissect nervous system function, including the synaptic regulation of dopamine signaling. Our lab has employed a forward genetic screen in C. elegans based on the dopamine-related behavior Swimming-induced paralysis (Swip) to identify swip-13, a novel genetic regulator of dopamine signaling. Genetic analysis of swip-13 mutants has revealed a role for this gene in dopamine neurons to positively regulate the activity of the presynaptic dopamine transporter DAT-1. swip-13 encodes an ortholog of the mammalian atypical MAP kinase ERK7/8, and work in human cell lines revealed a conserved role for human ERK8 in regulating the human dopamine transporter DAT. Furthermore, recent evidence supports a role for the small GTPase Rho in mediating the regulation of DAT by ERK8.