[Multiple functions of glutamate transporter EAAC1 in motor neurons]

The neuronal glutamate transporter EAAC1 localizes on neuronal cell membrane and uptakes glutamate from extracellular space. This function is crucial for the termination of glutamate-mediated signaling in synapse and also for prevention of neuronal death by suppressing glutamate toxicity. However, the possible mechanism of EAAC1 in preventing neuron death had not been resolved as compared with glial glutamate transporters such as GLT-1. Recently some groups revealed its additional mechanisms in terms of neuronal protection. In this review we introduce a unique "rescue" function of EAAC1, which is independent of clearance of extracellular glutamate. We recently identified that the decreased expression of EAAC1 following nerve injury in motor neuron was observed in mouse but not in rat, and the suppression in mouse was associated with motor neuron death seen in the mouse. This phenomenon leaded us to identification of a novel mechanism underlying the neuronal protection of EAAC1. 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 motor neurons from NGF deprivation and nerve injury. These facts imply that the EAAC1 has multiple mechanisms in prevention of neuron death.