Unique anti-apoptotic activity of EAAC1 in injured motor neurons

EMBO J. 2006 Jul 26;25(14):3411-21. doi: 10.1038/sj.emboj.7601225. Epub 2006 Jul 13.


Injured motor neurons of the adult rat can survive, whereas similar axotomy causes gradual motor neuron death in the adult mouse. We report that the decreased expression of the neuronal glutamate transporter excitatory amino-acid carrier 1 (EAAC1) following nerve injury is associated with motor neuron death in the mouse. Glutamate transporters play a crucial role in prevention of neuronal death by suppressing glutamate toxicity. However, the possible functional role of EAAC1 in preventing neuron death has not been resolved as compared with glial glutamate transporters such as GLT-1. Here, we have revealed a unique 'rescue' function of EAAC1, which is independent of removal of extracellular glutamate. During apoptotic stimuli, a mitochondrial protein, holocytochrome c synthetase (HCCS), translocates to outside the mitochondria, binds to and suppresses the X-linked inhibitor of apoptosis protein (XIAP), leading to activation of caspase-3. The N-terminus of EAAC1 can bind to HCCS, which interferes with the HCCS-XIAP association, and thereby maintain XIAP activity. This unique anti-apoptotic mechanism of EAAC1 functions in rescuing PC12 cells and motor neurons from NGF deprivation and nerve injury, respectively.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Apoptosis / physiology*
  • Axotomy
  • Cells, Cultured
  • Excitatory Amino Acid Transporter 3 / deficiency
  • Excitatory Amino Acid Transporter 3 / genetics
  • Excitatory Amino Acid Transporter 3 / metabolism
  • Excitatory Amino Acid Transporter 3 / physiology*
  • Lyases / metabolism
  • Lyases / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred ICR
  • Mice, Transgenic
  • Motor Neurons / enzymology
  • Motor Neurons / pathology*
  • Neuronal Apoptosis-Inhibitory Protein / genetics
  • Neuronal Apoptosis-Inhibitory Protein / metabolism
  • Neuronal Apoptosis-Inhibitory Protein / physiology*
  • PC12 Cells
  • Rats
  • Rats, Wistar


  • Excitatory Amino Acid Transporter 3
  • Neuronal Apoptosis-Inhibitory Protein
  • Slc1a1 protein, mouse
  • Slc1a1 protein, rat
  • Lyases
  • cytochrome C synthetase