The NR1 M3 Domain Mediates Allosteric Coupling in the<i>N</i>-Methyl-D-aspartate Receptor

Blanke, Marie L.; VanDongen, Antonius M.J.

doi:10.1124/mol.107.044115

Cited by 22 publications

(27 citation statements)

References 68 publications

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“…An increase in LBD cleft closure upon channel opening (Fig. 6 B) is supported by direct evidence from Blanke and VanDongen (47). These authors found that mutations at a conserved position (referred to as A7) near the N-terminus of the GluN1 M3 helix increased the preference of the channel for the open state, and at the same time also decreased the accessibility to the LBD cleft.…”

Section: Discussionsupporting

confidence: 66%

Semiclosed Conformations of the Ligand-Binding Domains of NMDA Receptors during Stationary Gating

Dai

Zhou

2016

Biophysical Journal

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NMDA receptors are tetrameric ligand-gated ion channels. In the continuous presence of saturating agonists, NMDA receptors undergo stationary gating, in which the channel stochastically switches between an open state that permits ion conductance and a closed state that prevents permeation. The ligand-binding domains (LBDs) of the four subunits are expected to have closed clefts in the channel-open state. On the other hand, there is little knowledge about the conformational status of the LBDs in the channel-closed state during stationary gating. To probe the latter conformational status, Kussius and Popescu engineered interlobe disulfide cross-links in NMDA receptors and found that the cross-linking produced stationary gating kinetics that differed only subtly from that produced by agonist binding. These authors assumed that the cross-linking immobilized the LBDs in cleft-closed conformations, and consequently concluded that throughout stationary gating, agonistbound LBDs also stayed predominantly in cleft-closed conformations and made only infrequent excursions to cleft-open conformations. Here, by calculating the conformational free energies of cross-linked and agonist-bound LBDs, we assess whether cross-linking actually traps the LBDs in cleft-closed conformations and delineate semiclosed conformations of agonist-bound LBDs that may potentially be thermodynamically and kinetically important during stationary gating. Our free-energy results show that the cross-linked LBDs are not locked in the fully closed form; rather, they sample semiclosed conformations almost as readily as the agonist-bound LBDs. Several lines of reasoning suggest that LBDs are semiclosed in the channel-closed state during stationary gating. Our free-energy simulations suggest possible structural details of such semiclosed LBD conformations, including intra-and intermolecular interactions that serve as alternatives to those in the cleft-closed conformations.

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Section: Discussionsupporting

confidence: 66%

Semiclosed Conformations of the Ligand-Binding Domains of NMDA Receptors during Stationary Gating

Dai

Zhou

2016

Biophysical Journal

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“…6E). We do not fully understand this difference between the subunits but it may be a manifestation of subunit-specific contributions to channel gating (e.g., (Banke and Traynelis, 2003; Blanke and VanDongen, 2008). Nevertheless, the key point here is that the strong correlation within a subunit strongly supports the idea that potentiation is being driven mainly by an increase in P o .…”

Section: Resultsmentioning

confidence: 99%

Specific Sites within the Ligand-Binding Domain and Ion Channel Linkers Modulate NMDA Receptor Gating

Talukder¹,

Borker²,

Wollmuth³

2010

J. Neurosci.

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Gating in the NMDA receptor is initiated in the extracellular ligand-binding domain (LBD) and is ultimately propagated via three linkers-S1-M1, M3-S2, and S2-M4 -to the ion channel. M3-S2 directly couples LBD movements into channel gating, but the functional and structural contributions of S1-M1 and S2-M4 to the overall gating process are unknown. A scan of substituted cysteines in and around the NMDA receptor S1-M1 and S2-M4 with a bulky cysteine-reactive reagent identified numerous positions that showed potentiation of glutamate-activated as well as leak currents. As indexed by MK801 (dizocilpine hydrogen maleate), an open channel blocker, this potentiation was attributable to an increase in open probability, an interpretation confirmed for a subset of positions with single-channel recordings. The magnitude of this gating effect, acting through S1-M1 or S2-M4, was dependent on the intrinsic gating properties of the NMDA receptors, being more effective in the inherently low open probability GluN2C-than the higher open probability GluN2A-subunit-containing receptors. For the majority of these potentiation positions, we propose that alteration of gating arises from steric destabilization of contact interfaces where close apposition of the contacting partners is necessary for efficient channel closure. Our results therefore indicate that the NMDA receptor S1-M1 and S2-M4 linkers are dynamic during gating and can modulate the overall energetics of this process. Furthermore, the results conceptualize a mechanistic, as well as a possible structural, framework for pharmacologically targeting the linkers through noncompetitive and subunit-specific modes of action.

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“…Nevertheless, the functional significance of the different conformers and how they might arise and be constrained during biosynthesis is unknown. In terms of functional properties, subunit-specific differences in the LBD-TMD linker structure may underlie subunit-specific contributions to ion permeation (Watanabe et al, 2002) and channel gating (Banke and Traynelis, 2003, Sobolevsky et al, 2007, Blanke and VanDongen, 2008a, b) (Kussius and Popescu, 2009). Recent work from our laboratory suggests that despite subunit-specific differences in the structure of the LBD-TMD linkers, NMDA receptors undergo concerted gating that appears tightly coupled at the level of these linkers (Talukder & Wollmuth, 2011, Journal of General Physiology, in press).…”

Section: Discussionmentioning

confidence: 99%

Arrangement of Subunits in Functional NMDA Receptors

Salussolia¹,

Prodromou²,

Borker³

et al. 2011

J. Neurosci.

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Ionotropic glutamate receptors (iGluRs), including the NMDA receptor subtype, are ligand-gated ion channels critical to fast signaling in the central nervous system. NMDA receptors are obligate heterotetramers composed of two GluN1 and typically two GluN2 subunits. However, the arrangement of GluN subunits in functional receptors—whether like subunits are adjacent to (N1/N1/N2/N2) or diagonal to (N1/N2/N1/N2) one another—remains unclear. Recently, a crystal structure of a homomeric AMPA receptor revealed that the four identical subunits adopt two distinct and subunit-specific conformations termed A/C and B/D with subunits of like conformations (e.g., A/C) diagonal to one another. In the structure, the two conformers were notable at the level of the linkers (S1-M1, M3-S2, and S2-M4) that join the ligand-binding domain to the transmembrane ion channel with the M3-S2 linker positioned more proximal to the central axis of the channel pore in the A/C conformation and S2-M4 more proximal in the B/D conformation. Using immunoblots and functional assays, we show that introduced cysteines in the M3/M3-S2 linker of GluN1, but not GluN2, show dimer formation and oxidation-induced changes in current amplitudes predictive of the A/C conformation. Conversely, introduced cysteines in the S2-M4 linker of GluN2, but not GluN1, showed similar functional effects suggesting that the GluN2 subunit adopts the B/D conformation. Thus, we show that NMDA receptors, like AMPA receptors, possess distinct subunit-specific conformations with GluN1 approximating the A/C and GluN2 the B/D conformation. GluN subunits are therefore positioned in a N1/N2/N1/N2 arrangement in functional NMDA receptors.

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The NR1 M3 Domain Mediates Allosteric Coupling in theN-Methyl-D-aspartate Receptor

Cited by 22 publications

References 68 publications

Semiclosed Conformations of the Ligand-Binding Domains of NMDA Receptors during Stationary Gating

Semiclosed Conformations of the Ligand-Binding Domains of NMDA Receptors during Stationary Gating

Specific Sites within the Ligand-Binding Domain and Ion Channel Linkers Modulate NMDA Receptor Gating

Arrangement of Subunits in Functional NMDA Receptors

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