TY - JOUR
T1 - Chimeric glutamate receptor subunits reveal the transmembrane domain is sufficient for NMDA receptor pore properties but some positive allosteric modulators require additional domains
AU - Wilding, Timothy J.
AU - Lopez, Melany N.
AU - Huettner, James E.
N1 - Publisher Copyright:
© 2016 the authors.
Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2016/8/24
Y1 - 2016/8/24
N2 - NMDA receptors are ligand-gated ion channels that underlie transmission at excitatory synapses and play an important role in regulating synaptic strength and stability. Functional NMDA receptors require two copies of the GluN1 subunit coassembled with GluN2 (and/or GluN3) subunits into a heteromeric tetramer. A diverse array of allosteric modulators can upregulate or downregulate NMDA receptor activity. These modulators include both synthetic compounds and endogenous modulators, such as cis-unsaturated fatty acids, 24(S)-hydroxycholesterol, and various neurosteroids. To evaluate the structural requirements for the formation and allosteric modulation of NMDA receptor pores, we have replaced portions of the rat GluN1, GluN2A, and GluN2B subunits with homologous segments from the rat GluK2 kainate receptor subunit. Our results with these chimeric constructs show that the NMDA receptor transmembrane domain is sufficient to account for most pore properties, but that regulation by some allosteric modulators requires additional cytoplasmic or extracellular domains.
AB - NMDA receptors are ligand-gated ion channels that underlie transmission at excitatory synapses and play an important role in regulating synaptic strength and stability. Functional NMDA receptors require two copies of the GluN1 subunit coassembled with GluN2 (and/or GluN3) subunits into a heteromeric tetramer. A diverse array of allosteric modulators can upregulate or downregulate NMDA receptor activity. These modulators include both synthetic compounds and endogenous modulators, such as cis-unsaturated fatty acids, 24(S)-hydroxycholesterol, and various neurosteroids. To evaluate the structural requirements for the formation and allosteric modulation of NMDA receptor pores, we have replaced portions of the rat GluN1, GluN2A, and GluN2B subunits with homologous segments from the rat GluK2 kainate receptor subunit. Our results with these chimeric constructs show that the NMDA receptor transmembrane domain is sufficient to account for most pore properties, but that regulation by some allosteric modulators requires additional cytoplasmic or extracellular domains.
KW - Carboxy terminal domain
KW - Docosahexaenoic acid
KW - Palmitoylation
UR - http://www.scopus.com/inward/record.url?scp=84983268821&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.0345-16.2016
DO - 10.1523/JNEUROSCI.0345-16.2016
M3 - Article
C2 - 27559165
AN - SCOPUS:84983268821
VL - 36
SP - 8815
EP - 8825
JO - Journal of Neuroscience
JF - Journal of Neuroscience
SN - 0270-6474
IS - 34
ER -