The non-adrenergic imidazoline-1 receptor protein nischarin is a key regulator of astrocyte glutamate uptake

Astrocytic GLT-1 is the main glutamate transporter involved in glutamate buffering in the brain, pivotal for glutamate removal at excitatory synapses to terminate neurotransmission and for preventing excitotoxicity. We show here that the surface expression and function of GLT-1 can be rapidly modulated through the interaction of its N-terminus with the nonadrenergic imidazoline-1 receptor protein, Nischarin. The phox domain of Nischarin is critical for interaction and internalization of surface GLT-1. Using live super-resolution imaging, we found that glutamate accelerated Nischarin-GLT-1 internalization into endosomal structures. The surface GLT-1 level increased in Nischarin knockout astrocytes, and this correlated with a significant increase in transporter uptake current. In addition, Nischarin knockout in astrocytes is neuroprotective against glutamate excitotoxicity. These data provide new molecular insights into regulation of GLT-1 surface level and function and suggest new drug targets for the treatment of neurological disorders. [Display omitted] •Nischarin phox domain interacts with the N-terminus of the glutamate transporter, GLT-1•Nischarin promotes internalization of GLT-1 to endosomes•Glutamate modulates GLT-1 surface levels by regulating the Nischarin-GLT-1 interaction•Nischarin loss enhances GLT-1 surface levels, transport currents, and neuroprotection Molecular biology; Molecular neuroscience; Cellular neuroscience; Cell biology