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Publication
The Atypical MAP Kinase SWIP-13/ERK8 Regulates Dopamine Transporters through a
Rho-Dependent Mechanism.
Authors Bermingham DP, Hardaway JA, Refai O, Marks CR, Snider SL, Sturgeon SM, Spencer
WC, Colbran RJ, Miller DM, Blakely RD
Submitted By Submitted Externally on 3/23/2018
Status Published
Journal The Journal of neuroscience : the official journal of the Society for Neuroscience
Year 2017
Date Published 9/1/2017
Volume : Pages 37 : 9288 - 9304
PubMed Reference 28842414
Abstract The neurotransmitter dopamine (DA) regulates multiple behaviors across
phylogeny, with disrupted DA signaling in humans associated with addiction,
attention-deficit/ hyperactivity disorder, schizophrenia, and Parkinson's
disease. The DA transporter (DAT) imposes spatial and temporal limits on DA
action, and provides for presynaptic DA recycling to replenish neurotransmitter
pools. Molecular mechanisms that regulate DAT expression, trafficking, and
function, particularlyin vivo, remain poorly understood, though recent studies
have implicated rho-linked pathways in psychostimulant action. To identify genes
that dictate the ability of DAT to sustain normal levels of DA clearance, we
pursued a forward genetic screen inCaenorhabditis elegansbased on the phenotype
swimming-induced paralysis (Swip), a paralytic behavior observed in
hermaphrodite worms with loss-of-functiondat-1mutations. Here, we report the
identity ofswip-13, which encodes a highly conserved ortholog of the human
atypical MAP kinase ERK8. We present evidence that SWIP-13 acts presynaptically
to insure adequate levels of surface DAT expression and DA clearance. Moreover,
we providein vitroandin vivoevidence supporting a conserved pathway involving
SWIP-13/ERK8 activation of Rho GTPases that dictates DAT surface expression and
function.SIGNIFICANCE STATEMENTSignaling by the neurotransmitter dopamine (DA)
is tightly regulated by the DA transporter (DAT), insuring efficient DA
clearance after release. Molecular networks that regulate DAT are poorly
understood, particularlyin vivoUsing a forward genetic screen in the
nematodeCaenorhabditis elegans, we implicate the atypical mitogen activated
protein kinase, SWIP-13, in DAT regulation. Moreover, we providein vitroandin
vivoevidence that SWIP-13, as well as its human counterpart ERK8, regulate DAT
surface availability via the activation of Rho proteins. Our findings implicate
a novel pathway that regulates DA synaptic availability and that may contribute
to risk for disorders linked to perturbed DA signaling. Targeting this pathway
may be of value in the development of therapeutics in such disorders.




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