C-terminal Domains of N-Methyl-d-aspartic Acid Receptor Modulate Unitary Channel Conductance and Gating

Maki, Bruce A.; Aman, Teresa K.; Amico-Ruvio, Stacy A.; Kussius, Cassandra L.; Popescu, Gabriela

doi:10.1074/jbc.m112.390013

Cited by 54 publications

(55 citation statements)

References 66 publications

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“…4B and Table 1) (23). We reported previously that chimeric N1/N2A 2BCTD receptors maintained high N1/N2A-like basal activity and displayed considerably lower kinetic variability compared with N1/N2B receptors (26,41). In contrast to wild-type N2A-containing receptors, PKI treatment produced a significant decrease in P o for chimeric receptors, and this occurred through a similar mechanism as the effects of PKI on N2B-containing receptors (Fig.…”

Section: Pka Inhibitors Reduced N1/n2b Receptor Current Bysupporting

confidence: 52%

“…For some experiments, we used a chimeric mouse subunit, N2A 2BCTD , which had residues 1-837 of N2A and 839 -1483 of N2B (gift from Martha ConstantinePaton) (23). Additional mutations included C-terminal truncations as follows: N1 stop , which terminates after Lys-838 and N2A stop , which terminates after Lys-844 (gifts from Gary Westbrook) (24,25); and N2B stop , which terminates at Gln-845, was generated previously (26). N1 S897A and N1 S897D were gifts from John Woodward (27).…”

Section: Methodsmentioning

confidence: 99%

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Separate Intramolecular Targets for Protein Kinase A Control N-Methyl-d-aspartate Receptor Gating and Ca2+ Permeability

Aman¹,

Maki

Ruffino³

et al. 2014

Journal of Biological Chemistry

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Background: PKA increases NMDA receptor responses and phosphorylates multiple residues on C-terminal domains (CTD). Results: PKA inhibition reduced gating through GluN2B CTD and reduced Ca 2ϩ permeability through GluN1 CTD. Conclusion: PKA controls NMDA receptor gating and Ca 2ϩ permeability through distinct sites. Significance: Dissecting the complex modulatory effects of PKA on NMDA receptors helps delineate fundamental mechanisms of synaptic regulation.

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Section: Pka Inhibitors Reduced N1/n2b Receptor Current Bysupporting

confidence: 52%

Section: Methodsmentioning

confidence: 99%

Separate Intramolecular Targets for Protein Kinase A Control N-Methyl-d-aspartate Receptor Gating and Ca2+ Permeability

Aman¹,

Maki

Ruffino³

et al. 2014

Journal of Biological Chemistry

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“…To avoid potential incompatibility between trafficking signals present in GluN2A and GluN2B CTDs and between CTD structures and spatial requirements for the C1/C2 interaction, we replaced the CTD of GluN2B with that of GluN2A (Figure 1A). The functional properties of GluN2B subunits containing the CTD of GluN2A are indistinguishable from those of wild type GluN2B (Maki et al, 2012; Punnakkal et al, 2012). Thus, we generated C1- and C2-tagged GluN2A and GluN2B subunits (2A C1 , 2A C2 , 2B AC1 , and 2B AC2 ) that only differ in the intracellular CTDs by the leucine zipper motifs (LZ1 and LZ2).…”

Section: Resultsmentioning

confidence: 84%

Distinct Functional and Pharmacological Properties of Triheteromeric GluN1/GluN2A/GluN2B NMDA Receptors

Hansen

Ogden

Yuan

et al. 2014

Neuron

256

386

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Summary NMDA receptors are tetrameric ligand-gated ion channels comprised of GluN1, GluN2, and GluN3 subunits. Two different GluN2 subunits have been identified in most NMDA receptor-expressing cells, and the majority of native receptors are triheteromers containing two GluN1 and two different GluN2. In contrast to diheteromeric NMDA receptors, little is known about the function of triheteromers. We developed a method to provide selective cell-surface expression of recombinant GluN1/GluN2A/GluN2B triheteromers, and compared properties of these receptors with those of GluN1/GluN2A and GluN1/GluN2B diheteromers. We show that glutamate deactivation of triheteromers is distinct from those of GluN1/GluN2A and GluN1/GluN2B, and reveal modulation of triheteromers by subunit-selective antagonists ifenprodil, CP-101,606, TCN-201, and extracellular Zn2+. Furthermore, kinetic measurements suggest variation in the ifenprodil binding site of triheteromers compared to GluN1/GluN2B diheteromers. This work provides new insight to the distinct properties of GluN1/GluN2A/GluN2B triheteromers, which are presumably the most abundant NMDA receptors in the adult forebrain.

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“…1C). It is also unlikely to stem from truncation of the GluN2 CTD since complete deletion of the GluN1 and/or GluN2 CTD does not prevent functional expression (Vissel et al, 2002;Puddifoot et al, 2009;Maki et al, 2012;Punnakkal et al, 2012). Therefore, GluN1/ GluN2Ar1 and GluN1/GluN2Br2 diheteromers do not express at the plasma membrane, likely because they are retained in the ER.…”

Section: Selective Expression Of Triheteromeric Nmdarsmentioning

confidence: 99%

Controlling NMDA Receptor Subunit Composition Using Ectopic Retention Signals

et al. 2014

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Ligand-gated ion channels (LGICs) mediate fast synaptic transmission in the CNS. Typically, these membrane proteins are multimeric complexes associating several homologous subunits around a central pore. Because of the large repertoire of subunits within each family,LGICs exist in vivo as multiple subtypes that differ in subunit composition and functional properties. Establishing the specific properties of individual receptor subtypes remains a major goal in the field of neuroscience and molecular pharmacology. However, isolating specific receptor subtype in recombinant systems can be problematic because of the mixture of receptor populations. This is the case for NMDA receptors (NMDARs), a large family of tetrameric glutamate-gated ion channels that play key roles in brain physiology and pathology. A significant fraction of native NMDARs are triheteromers composed of two GluN1 subunits and two different GluN2 subunits (GluN2A-D). We developed a method based on dual retention signals adapted from G-protein-coupled GABA-B receptors allowing exclusive cell surface expression of triheteromeric rat NMDARs while coexpressed diheteromeric receptors (which contain a single type of GluN2 subunit) are retained intracellularly. Using this approach, we determined the functional properties of GluN1/GluN2A/GluN2B triheteromers, one of the most abundant NMDAR subtypes in the adult forebrain, revealing their unique gating and pharmacological attributes. We envision applicability of the retention signal approach for the study of a variety of heteromeric glutamate-gated ion channel receptors with defined subunit composition.

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C-terminal Domains of N-Methyl-d-aspartic Acid Receptor Modulate Unitary Channel Conductance and Gating

Cited by 54 publications

References 66 publications

Separate Intramolecular Targets for Protein Kinase A Control N-Methyl-d-aspartate Receptor Gating and Ca2+ Permeability

Separate Intramolecular Targets for Protein Kinase A Control N-Methyl-d-aspartate Receptor Gating and Ca2+ Permeability

Distinct Functional and Pharmacological Properties of Triheteromeric GluN1/GluN2A/GluN2B NMDA Receptors

Controlling NMDA Receptor Subunit Composition Using Ectopic Retention Signals

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