Positive Allosteric Modulators of GluN2A-Containing NMDARs with Distinct Modes of Action and Impacts on Circuit Function

Hackos, David H.; Lupardus, P.J.; Grand, Teddy; Chen, Yelin; Wang, Tzu-Ming; Reynen, Paul; Gustafson, Amy; Wallweber, Heidi J.A.; Volgraf, Matthew; Sellers, Benjamin D.; Schwarz, Jacob B.; Paoletti, Pierre; Sheng, Morgan; Zhou, Qiang; Hanson, Jesse E.

doi:10.1016/j.neuron.2016.01.016

Cited by 149 publications

(247 citation statements)

References 58 publications

(71 reference statements)

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“…Considerable progress has been made in the development of subunit-selective allosteric modulators (7)(8)(9)(10)(11)(12)(13), but the development of subtype-selective competitive NMDA receptor antagonists has been less successful. The competitive glutamate-site antagonist NVP-AAM077 (hereafter NVP) was originally reported to have 100-fold preference for GluN1/2A over GluN1/2B (14).…”

mentioning

confidence: 99%

Structural basis of subunit selectivity for competitive NMDA receptor antagonists with preference for GluN2A over GluN2B subunits

Lind

Mou

Tamborini

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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NMDA-type glutamate receptors are ligand-gated ion channels that contribute to excitatory neurotransmission in the central nervous system (CNS). Most NMDA receptors comprise two glycine-binding GluN1 and two glutamate-binding GluN2 subunits (GluN2A–D). We describe highly potent (S)-5-[(R)-2-amino-2-carboxyethyl]-4,5-dihydro-1H-pyrazole-3-carboxylic acid (ACEPC) competitive GluN2 antagonists, of which ST3 has a binding affinity of 52 nM at GluN1/2A and 782 nM at GluN1/2B receptors. This 15-fold preference of ST3 for GluN1/2A over GluN1/2B is improved compared with NVP-AAM077, a widely used GluN2A-selective antagonist, which we show has 11-fold preference for GluN1/2A over GluN1/2B. Crystal structures of the GluN1/2A agonist binding domain (ABD) heterodimer with bound ACEPC antagonists reveal a binding mode in which the ligands occupy a cavity that extends toward the subunit interface between GluN1 and GluN2A ABDs. Mutational analyses show that the GluN2A preference of ST3 is primarily mediated by four nonconserved residues that are not directly contacting the ligand, but positioned within 12 Å of the glutamate binding site. Two of these residues influence the cavity occupied by ST3 in a manner that results in favorable binding to GluN2A, but occludes binding to GluN2B. Thus, we reveal opportunities for the design of subunit-selective competitive NMDA receptor antagonists by identifying a cavity for ligand binding in which variations exist between GluN2A and GluN2B subunits. This structural insight suggests that subunit selectivity of glutamate-site antagonists can be mediated by mechanisms in addition to direct contributions of contact residues to binding affinity.

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mentioning

confidence: 99%

Structural basis of subunit selectivity for competitive NMDA receptor antagonists with preference for GluN2A over GluN2B subunits

Lind

Mou

Tamborini

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…There, synapses host an NGIC compliment kinetically suited to their input patterns (14) but are also capable of dynamically shifting between the priorities of integration and precision (8). Unsurprisingly then, influencing the deactivation kinetics of specific NGIC subtypes using allosteric modulators is a promising therapeutic objective (15)(16)(17).…”

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confidence: 99%

Deactivation kinetics of acid-sensing ion channel 1a are strongly pH-sensitive

MacLean

Jayaraman

2017

Proc. Natl. Acad. Sci. U.S.A.

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Acid-sensing ion channels (ASICs) are trimeric cation-selective ion channels activated by protons in the physiological range. Recent reports have revealed that postsynaptically localized ASICs contribute to the excitatory postsynaptic current by responding to the transient acidification of the synaptic cleft that accompanies neurotransmission. In response to such brief acidic transients, both recombinant and native ASICs show extremely rapid deactivation in outside-out patches when jumping from a pH 5 stimulus to a single resting pH of 8. Given that the resting pH of the synaptic cleft is highly dynamic and depends on recent synaptic activity, we explored the kinetics of ASIC1a and 1a/2a heteromers to such brief pH transients over a wider [H + ] range to approximate neuronal conditions better. Surprisingly, the deactivation of ASICs was steeply dependent on the pH, spanning nearly three orders of magnitude from extremely fast (<1 ms) at pH 8 to very slow (>300 ms) at pH 7. This study provides an example of a ligand-gated ion channel whose deactivation is sensitive to agonist concentrations that do not directly activate the receptor. Kinetic simulations and further mutagenesis provide evidence that ASICs show such steeply agonist-dependent deactivation because of strong cooperativity in proton binding. This capacity to signal across such a large synaptically relevant bandwidth enhances the response to smallamplitude acidifications likely to occur at the cleft and may provide ASICs with the ability to shape activity in response to the recent history of the synapse.acid-sensing ion channel | gating | kinetics | ligand-gated ion channel N eurotransmitter levels within the synaptic cleft rise and fall very rapidly, with clearance times generally on the order of a few hundred microseconds to 2 ms (1-3). However, the duration of responses from neurotransmitter-gated ion channels (NGICs) varies widely across several orders of magnitude depending on the receptors involved. For example, in certain regions, glutamatergic excitatory postsynaptic currents (EPSCs) decay with submillisecond time constants (4), but the EPSCs of GluN2D-containing NMDA receptors decay over roughly 200 ms (5, 6). Such differences in the decay or deactivation of NGIC responses can profoundly impact the window of synaptic excitability and integration (4,7,8). Control over NGIC kinetics is also a powerful force during development, where slower receptor subtypes tend to be used early on, broadening the window of plasticity during critical periods, and later give way to faster decaying subunits providing greater temporal precision (9-13). This trade-off between the window of integration on the one hand and temporal precision on the other persists in the mature brain. There, synapses host an NGIC compliment kinetically suited to their input patterns (14) but are also capable of dynamically shifting between the priorities of integration and precision (8). Unsurprisingly then, influencing the deactivation kinetics of specific NGIC subtypes using allosteri...

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“…Elevated agonist concentrations can increase a modulator’s potency and conversely a PAM can increase agonist potency, as seen for SGE201 (Linsenbardt et al, 2014) and GNE-8324 (Hackos et al, 2016). In such cases, saturating agonist concentrations may mask potentiating activity if the primary PAM action is to increase agonist occupation.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast to agents that potentiate NMDARs containing specific GluN2 subunits, e.g. pregnenalone sulphate (PS) (Horak et al, 2006), UBP710 -GluN2A/GluN2B; UBP512 - GluN2A (Costa et al, 2010); GNE-8324 - GluN2A (Hackos et al, 2016); CIQ – GluN2C/GluN2D (Mullasseril et al, 2010); PYD-106 – GluN2C (Khatri et al, 2014), the phenanthroic acid derivative UBP646 (Costa et al, 2010) and the cholesterol derivative SGE-201 (Paul et al, 2013) potentiate all four GluN1/GluN2 subtypes. Thus, in cases where it would be useful to augment global NMDAR function, agents with these properties may be beneficial.…”

Section: Introductionmentioning

confidence: 99%

Mechanism and properties of positive allosteric modulation of N -methyl- d -aspartate receptors by 6-alkyl 2-naphthoic acid derivatives

et al. 2017

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The theory that N-methyl-D-aspartate receptor (NMDAR) hypofunction is responsible for the symptoms of schizophrenia is well supported by many pharmacological and genetic studies. Accordingly, positive allosteric modulators (PAMs) that augment NMDAR signaling may be useful for treating schizophrenia. Previously we have identified several NMDAR PAMs containing a carboxylic acid attached to naphthalene, phenanthrene, or coumarin ring systems. In this study, we describe several functional and mechanistic properties of UBP684, a 2-naphthoic acid derivative, which robustly potentiates agonist responses at each of the four GluN1a/GluN2 receptors and at neuronal NMDARs. UBP684 increases the maximal L-glutamate/glycine response while having minor subunit-specific effects on agonist potency. PAM binding is independent of agonist binding, and PAM activity is independent of membrane voltage, redox state, and the GluN1 exon 5 N-terminal insert. UBP684 activity is, however, markedly pH-dependent, with greater potentiation occurring at lower pHs and inhibitory activity at pH 8.4. UBP684 increases channel open probability (Po) and slows receptor deactivation time upon removal of L-glutamate, but not glycine. The structurally related PAM, UBP753, reproduced most of these findings, but did not prolong agonist removal deactivation time. Studies using cysteine mutants to lock the GluN1 and GluN2 ligand-binding domains (LBDs) in the agonist-bound states indicate that PAM potentiation requires GluN2 LBD conformational flexibility. Together, these findings suggest that UBP684 and UBP753 stabilize the GluN2 LBD in an active conformation and thereby increase Po. Thus, UBP684 and UBP753 may serve as lead compounds for developing agents to enhance NMDAR activity in disorders associated with NMDAR hypofunction.

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Positive Allosteric Modulators of GluN2A-Containing NMDARs with Distinct Modes of Action and Impacts on Circuit Function

Cited by 149 publications

References 58 publications

Structural basis of subunit selectivity for competitive NMDA receptor antagonists with preference for GluN2A over GluN2B subunits

Structural basis of subunit selectivity for competitive NMDA receptor antagonists with preference for GluN2A over GluN2B subunits

Deactivation kinetics of acid-sensing ion channel 1a are strongly pH-sensitive

Mechanism and properties of positive allosteric modulation of N -methyl- d -aspartate receptors by 6-alkyl 2-naphthoic acid derivatives

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