Role of Neto1 extracellular domain in modulation of kainate receptors

Rajesh Vinnakota, Surbhi Dhingra, Jyoti Kumari, Mohammed Yousuf Ansari, Ekta Shukla, Mayuri Dattatray Nerkar, Janesh Kumar

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Kainate receptors play fundamental roles in regulating synaptic transmission and plasticity in central nervous system and are regulated by their cognate auxiliary subunits Neuropilin and tolloid-like proteins 1 and 2 (Neto). While electrophysiology-based insights into functions of Neto proteins are known, biophysical and biochemical studies into Neto proteins have been largely missing till-date. Our biochemical, biophysical, and functional characterization of the purified extracellular domain (ECD) of Neto1 shows that Neto1-ECD exists as monomers in solution and has a micromolar affinity for GluK2 receptors in apo state or closed state. Remarkably, the affinity was ~2.8 fold lower for receptors trapped in the desensitized state, highlighting the conformation-dependent interaction of Neto proteins with kainate receptors. SAXS analysis of Neto1-ECD reveals that their dimensions are long enough to span the entire extracellular domain of kainate receptors. The shape and conformation of Neto1-ECD seems to be altered by calcium ions pointing towards its possible role in modulating Neto1 functions. Functional assays using GluK2 receptors and GluK2/GluA2 chimeric receptors reveal a differential role of Neto1 domains in modulating receptor functions. Although the desensitization rate was not affected by the Neto1-ECD, the recovery rates from the desensitized state are altered.

Original languageEnglish
Pages (from-to)525-536
Number of pages12
JournalInternational Journal of Biological Macromolecules
Volume192
DOIs
StatePublished - 1 Dec 2021
Externally publishedYes

Keywords

  • Auxiliary subunit
  • Ion channel
  • Ionotropic glutamate receptor
  • Kainate
  • Membrane protein
  • Neto1
  • Neurotransmitter receptor
  • Synaptic plasticity

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