Format

Send to

Choose Destination
J Gen Physiol. 2017 Jun 5;149(6):661-680. doi: 10.1085/jgp.201711762. Epub 2017 May 15.

Divergent roles of a peripheral transmembrane segment in AMPA and NMDA receptors.

Author information

1
Graduate Program in Cellular and Molecular Pharmacology, Stony Brook University, Stony Brook, NY 11794.
2
Medical Scientist Training Program (MSTP), Stony Brook University, Stony Brook, NY 11794.
3
Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY 11794.
4
Department of Pediatrics, Pediatrics Residency Program, Stony Brook University, Stony Brook, NY 11794.
5
Graduate Program in Neuroscience, Stony Brook University, Stony Brook, NY 11794.
6
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
7
Department of Physics, Florida State University, Tallahassee, FL 32306.
8
Institute of Molecular Biophysics, Florida State University, Tallahassee, FL 32306.
9
Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY 11794.
10
Department of Neurobiology and Behavior, Stony Brook University, Stony Brook, NY 11794 lonnie.wollmuth@stonybrook.edu.
11
Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794.

Abstract

Ionotropic glutamate receptors (iGluRs), including AMPA receptor (AMPAR) and NMDA receptor (NMDAR) subtypes, are ligand-gated ion channels that mediate signaling at the majority of excitatory synapses in the nervous system. The iGluR pore domain is structurally and evolutionarily related to an inverted two-transmembrane K+ channel. Peripheral to the pore domain in eukaryotic iGluRs is an additional transmembrane helix, the M4 segment, which interacts with the pore domain of a neighboring subunit. In AMPARs, the integrity of the alignment of a specific face of M4 with the adjacent pore domain is essential for receptor oligomerization. In contrast to AMPARs, NMDARs are obligate heterotetramers composed of two GluN1 and typically two GluN2 subunits. Here, to address the function of the M4 segments in NMDARs, we carry out a tryptophan scan of M4 in GluN1 and GluN2A subunits. Unlike AMPARs, the M4 segments in NMDAR subunits makes only a limited contribution to their biogenesis. However, the M4 segments in both NMDAR subunits are critical for receptor activation, with mutations at some positions, most notably at the extreme extracellular end, completely halting the gating process. Furthermore, although the AMPAR M4 makes a minimal contribution to receptor desensitization, the NMDAR M4 segments have robust and subunit-specific effects on desensitization. These findings reveal that the functional roles of the M4 segments in AMPARs and NMDARs have diverged in the course of their evolution and that the M4 segments in NMDARs may act as a transduction pathway for receptor modulation at synapses.

PMID:
28507080
PMCID:
PMC5460951
DOI:
10.1085/jgp.201711762
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center