The auxiliary subunits Neto1 and Neto2 have distinct, subunit-dependent effects at recombinant GluK1- and GluK2-containing kainate receptors

Neuropharmacology. 2015 Dec:99:471-80. doi: 10.1016/j.neuropharm.2015.08.018. Epub 2015 Aug 13.


The kainate-type of ionotropic glutamate receptors are assembled from a combination of five different pore-forming subunits (GluK1-5), which confer distinct functional and pharmacological properties. These receptors are also modulated by co-assembly with the auxiliary subunits Neto1 and Neto2. To determine the impact of variation in subunit composition on the functional interaction between kainate receptors and Neto subunits, the Neto subunits were combined with either GluK1 or GluK2 in HEK-293T cells and responses to glutamate examined through patch-clamp recordings. Co-expression of GluK1 with either Neto1 or Neto2 caused a substantial increase in glutamate sensitivity and a slowing of the onset of desensitization at low agonist concentrations. However, at higher glutamate concentrations the primary effect of Neto2 was to slow the onset of desensitization, while that of Neto1 was to increase recovery from desensitization. In contrast, co-expression of Neto2 with GluK2 homomeric receptors had only modest effects on glutamate sensitivity, but increased the rate of recovery from desensitization as well as slowing its onset at all agonist concentrations. The properties of chimeric Neto1/Neto2 subunits suggested that the extracellular N-terminal region including the two CUB domains was largely responsible for the distinct regulatory effects of Neto1 and Neto2 on the desensitization properties of GluK1 homomeric receptors. These results further demonstrate that the functional effects of Neto subunits depend upon the subunit identity of both the auxiliary and the pore-forming subunits.

Keywords: Auxiliary subunits; Glutamate receptors; Ionotropic; Kainate receptors; Neto; Recombinant.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dose-Response Relationship, Drug
  • Excitatory Amino Acid Agents / pharmacology
  • GluK2 Kainate Receptor
  • Glutamic Acid / metabolism*
  • Glutamic Acid / pharmacology
  • HEK293 Cells
  • Humans
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Patch-Clamp Techniques
  • Receptors, Kainic Acid / genetics
  • Receptors, Kainic Acid / metabolism*
  • Receptors, N-Methyl-D-Aspartate
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism


  • Excitatory Amino Acid Agents
  • Gluk1 kainate receptor
  • Membrane Proteins
  • NETO1 protein, human
  • NETO2 protein, human
  • Receptors, Kainic Acid
  • Receptors, N-Methyl-D-Aspartate
  • Recombinant Proteins
  • Glutamic Acid