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

Swati Gupta; Narges Bazargani; James Drew; Jack H Howden; Souvik Modi; Sana Al Awabdh; Hélène Marie; David Attwell; Josef T Kittler

doi:10.1016/j.isci.2022.104127

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

iScience. 2022 Mar 21;25(4):104127. doi: 10.1016/j.isci.2022.104127. eCollection 2022 Apr 15.

Authors

Swati Gupta¹, Narges Bazargani¹, James Drew¹, Jack H Howden¹, Souvik Modi¹, Sana Al Awabdh¹, Hélène Marie¹, David Attwell¹, Josef T Kittler¹

Affiliation

¹ Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, WC1E 6BT London, UK.

Abstract

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.

Keywords: Cell biology; Cellular neuroscience; Molecular biology; Molecular neuroscience.

Grants and funding

WT_/Wellcome Trust/United Kingdom