Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits.
The N-methyl-D-aspartate subtype of glutamate receptor (NMDAR) serves critical functions in physiological and pathological processes in the central nervous system, including neuronal development, plasticity and neurodegeneration. Conventional heteromeric NMDARs composed of NR1 and NR2A-D subunits require dual agonists, glutamate and glycine, for activation. They are also highly permeable to Ca2+, and exhibit voltage-dependent inhibition by Mg2+. Coexpression of NR3A with NR1 and NR2 subunits modulates NMDAR activity. Here we report the cloning and characterization of the final member of the NMDAR family, NR3B, which shares high sequence homology with NR3A. From in situ and immunocytochemical analyses, NR3B is expressed predominantly in motor neurons, whereas NR3A is more widely distributed. Remarkably, when co-expressed in Xenopus oocytes, NR3A or NR3B co-assembles with NR1 to form excitatory glycine receptors that are unaffected by glutamate or NMDA, and inhibited by D-serine, a co-activator of conventional NMDARs. Moreover, NR1/NR3A or -3B receptors form relatively Ca2+-impermeable cation channels that are resistant to Mg2+, MK-801, memantine and competitive antagonists. In cerebrocortical neurons containing NR3 family members, glycine triggers a burst of firing, and membrane patches manifest glycine-responsive single channels that are suppressible by D-serine. By itself, glycine is normally thought of as an inhibitory neurotransmitter. In contrast, these NR1/NR3A or -3B 'NMDARs' constitute a type of excitatory glycine receptor.
Chatterton
Jon E
JE
Center for Neuroscience and Aging, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.
Awobuluyi
Marc
M
Premkumar
Louis S
LS
Takahashi
Hiroto
H
Talantova
Maria
M
Shin
Yeonsook
Y
Cui
Jiankun
J
Tu
Shichun
S
Sevarino
Kevin A
KA
Nakanishi
Nobuki
N
Tong
Gang
G
Lipton
Stuart A
SA
Zhang
Dongxian
D
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002413:Cations, Divalent / Q000378:metabolism; D002490:Central Nervous System / Q000166:cytology / Q000378:metabolism; D003001:Cloning, Molecular; D004594:Electrophysiology; D018698:Glutamic Acid / Q000494:pharmacology; D005998:Glycine / Q000494:pharmacology; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D017136:Ion Transport / Q000187:drug effects; D008274:Magnesium / Q000378:metabolism; D008969:Molecular Sequence Data; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D021122:Protein Subunits; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D051381:Rats; D018009:Receptors, Glycine / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017385:Sequence Homology; D012694:Serine / Q000494:pharmacology; D013379:Substrate Specificity; D014982:Xenopus laevis
D002413:Cations, Divalent; D021122:Protein Subunits; D012333:RNA, Messenger; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D012694:Serine; D016202:N-Methylaspartate; D008274:Magnesium; D002118:Calcium; D005998:Glycine