The atypical MAP kinase SWIP-13/ERK8 regulates dopamine transporters through a Rho-dependent mechanism

Academic Article

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, particularly in 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 in Caenorhabditis elegans based on the phenotype swimming-induced paralysis (Swip), a paralytic behavior observed in hermaphrodite worms with loss-of-function dat-1 mutations. Here, we report the identity of swip-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 provide in vitro and in vivo evidence supporting a conserved pathway involving SWIP-13/ERK8 activation of Rho GTPases that dictates DAT surface expression and function.
  • Published In

    Digital Object Identifier (doi)

    Author List

  • Bermingham DP; Hardaway JA; Refai O; Marks CR; Snider SL; Sturgeon SM; Spencer WC; Colbran RJ; Miller DM; Blakely RD
  • Start Page

  • 9288
  • End Page

  • 9304
  • Volume

  • 37
  • Issue

  • 38