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

iScience (Apr 2022)

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

Affiliations

Swati Gupta: Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, WC1E 6BT London, UK
Narges Bazargani: Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, WC1E 6BT London, UK
James Drew: Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, WC1E 6BT London, UK
Jack H. Howden: Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, WC1E 6BT London, UK
Souvik Modi: Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, WC1E 6BT London, UK
Sana Al Awabdh: Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, WC1E 6BT London, UK
Hélène Marie: Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, WC1E 6BT London, UK
David Attwell: Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, WC1E 6BT London, UK
Josef T. Kittler: Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, WC1E 6BT London, UK; Corresponding author

Journal volume & issue: Vol. 25, no. 4
p. 104127

Abstract

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Summary: 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.

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

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