Influence of the TARP γ8-Selective Negative Allosteric Modulator JNJ-55511118 on AMPA Receptor Gating and Channel Conductance

Coombs, Ian D.; Sexton, Craig A.; Cull-Candy, SG; Farrant, M

doi:10.1124/molpharm.121.000473

Cited by 5 publications

(5 citation statements)

References 65 publications

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“…6b and Supplementary Fig. 9a, b ), consistent with a recent study 39 . Similar to JNJ-118, LY-481 triggered a pronounced reduction of the equilibrium response, but modestly slowed GluA2_γ8 desensitization kinetics (Fig.…”

Section: Resultssupporting

confidence: 92%

“…MD simulations reveal water molecules penetrating into the pocket from γ8 Ser128 on the extracellular edge down to γ8 Asn172 in the binding pocket (Supplementary Fig. 4a ), suggesting a potential route for ligand entry, with access via the lipid bilayer offering an additional route , , as also suggested in a recent study of JNJ-118 39 . Putative waters appear in the LY-481 cryoEM map around GluA2 Ser790, and in the NAM pocket at γ8 Ser128 (Supplementary Fig.…”

Section: Resultssupporting

confidence: 71%

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Modulatory mechanisms of TARP γ8-selective AMPA receptor therapeutics

et al. 2023

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AMPA glutamate receptors (AMPARs) mediate excitatory neurotransmission throughout the brain. Their signalling is uniquely diversified by brain region-specific auxiliary subunits, providing an opportunity for the development of selective therapeutics. AMPARs associated with TARP γ8 are enriched in the hippocampus, and are targets of emerging anti-epileptic drugs. To understand their therapeutic activity, we determined cryo-EM structures of the GluA1/2-γ8 receptor associated with three potent, chemically diverse ligands. We find that despite sharing a lipid-exposed and water-accessible binding pocket, drug action is differentially affected by binding-site mutants. Together with patch-clamp recordings and MD simulations we also demonstrate that ligand-triggered reorganisation of the AMPAR-TARP interface contributes to modulation. Unexpectedly, one ligand (JNJ-61432059) acts bifunctionally, negatively affecting GluA1 but exerting positive modulatory action on GluA2-containing AMPARs, in a TARP stoichiometry-dependent manner. These results further illuminate the action of TARPs, demonstrate the sensitive balance between positive and negative modulatory action, and provide a mechanistic platform for development of both positive and negative selective AMPAR modulators.

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Section: Resultssupporting

confidence: 92%

Section: Resultssupporting

confidence: 71%

Modulatory mechanisms of TARP γ8-selective AMPA receptor therapeutics

et al. 2023

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“…This behaviour was not seen with JNJ-118, which acted as a NAM on GluA2 for all measures ( Fig. S9a and b ), consistent with a recent study 48 . Similar to JNJ-118, LY-481 triggered a pronounced reduction of the equilibrium response, but modestly slowed GluA2_γ8 desensitization kinetics ( Fig.…”

Section: Resultssupporting

confidence: 92%

Modulatory mechanisms of TARP γ8-selective AMPA receptor therapeutics

Zhang

Lape

Shaikh

et al. 2022

Preprint

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AMPA glutamate receptors (AMPARs) mediate excitatory neurotransmission throughout the brain. Their signalling is uniquely diversified by brain region-specific auxiliary subunits, providing an opportunity for the development of selective therapeutics. AMPARs associated with TARP γ8 are enriched in the hippocampus, and are targets of emerging anti-epileptic drugs. To understand their therapeutic activity, we determined cryo-EM structures of the GluA1/2-γ8 receptor associated with three potent, chemically diverse drugs. We find that despite sharing a lipid-exposed and water-accessible binding pocket, drug action is differentially affected by binding-site mutants. Together with patch-clamp recordings and MD simulations we demonstrate that ligand-triggered reorganisation of the AMPAR-TARP interface contributes to modulation. Unexpectedly, one ligand (JNJ-61432059) acts bifunctionally, negatively affecting GluA1 but exerting positive modulatory action on GluA2-containing AMPARs, in a TARP stoichiometry-dependent manner. These results further illuminate the action of TARPs, demonstrate the sensitive balance between positive and negative modulatory action, and provide a mechanistic platform for development of both positive and negative selective AMPAR modulators.

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“…7a, b ). The promoting effect of JNJ55511118 on the desensitization of AMPARs was also consistent with a recent report, which identified that JNJ55511118 decreased peak currents and the time constant of desensitization of AMPARs 25 . Taken together, these results provide important insights into the rapid antidepressant effects of ketamine that is dependent on the potentiation of TARP-γ8-selective AMPAR-mediated synaptic transmission in the ventral hippocampus.…”

Section: Resultssupporting

confidence: 91%

“…A series of TARP-γ8 antagonists have been designed and synthesized, such as LY3130481 and JNJ55511118, which selectively antagonize AMPAR containing TARP-γ8, but not other TARP members 24 , 25 , 60 . Corresponding to this selective activity, LY3130481 was proved to prevent multiple epilepsy-related symptoms in mice without motor side effects 60 .…”

Section: Discussionmentioning

confidence: 99%

Enhanced TARP-γ8-PSD-95 coupling in excitatory neurons contributes to the rapid antidepressant-like action of ketamine in male mice

Xue,

He,

et al. 2023

Nat Commun

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Ketamine produces rapid antidepressant effects at sub-anesthetic dosage through early and sustained activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), however, the exact molecular mechanism still remains unclear. Transmembrane AMPAR regulatory protein-γ8 (TARP-γ8) is identified as one of AMPAR auxiliary subunits, which controls assemblies, surface trafficking and gating of AMPARs. Here, we show that ketamine rescues both depressive-like behaviors and the decreased AMPARs-mediated neurotransmission by recruitment of TARP-γ8 at the postsynaptic sites in the ventral hippocampus of stressed male mice. Furthermore, the rapid antidepressant effects of ketamine are abolished by selective blockade of TARP-γ8-containing AMPAR or uncoupling of TARP-γ8 from PSD-95. Overexpression of TARP-γ8 reverses chronic stress-induced depressive-like behaviors and attenuation of AMPARs-mediated neurotransmission. Conversely, knockdown of TARP-γ8 in excitatory neurons prevents the rapid antidepressant effects of ketamine.

show abstract

Influence of the TARP γ8-Selective Negative Allosteric Modulator JNJ-55511118 on AMPA Receptor Gating and Channel Conductance

Cited by 5 publications

References 65 publications

Modulatory mechanisms of TARP γ8-selective AMPA receptor therapeutics

Modulatory mechanisms of TARP γ8-selective AMPA receptor therapeutics

Modulatory mechanisms of TARP γ8-selective AMPA receptor therapeutics

Enhanced TARP-γ8-PSD-95 coupling in excitatory neurons contributes to the rapid antidepressant-like action of ketamine in male mice

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