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Biased modulators of NMDA receptors control channel opening and ion selectivity

Abstract

Allosteric modulators of ion channels typically alter the transitions rates between conformational states without changing the properties of the open pore. Here we describe a new class of positive allosteric modulators of N-methyl d-aspartate receptors (NMDARs) that mediate a calcium-permeable component of glutamatergic synaptic transmission and play essential roles in learning, memory and cognition, as well as neurological disease. EU1622-14 increases agonist potency and channel-open probability, slows receptor deactivation and decreases both single-channel conductance and calcium permeability. The unique functional selectivity of this chemical probe reveals a mechanism for enhancing NMDAR function while limiting excess calcium influx, and shows that allosteric modulators can act as biased modulators of ion-channel permeation.

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Fig. 1: EU1622-1 is a positive allosteric NMDAR modulator.
Fig. 2: EU1622-1 reduces single-channel conductance for GluN1–GluN2B NMDARs.
Fig. 3: EU1622-14 prolongs the response deactivation time course and reduces channel conductance of NMDARs.
Fig. 4: EU1622-14 reduces native NMDAR conductance.
Fig. 5: EU1622-14 reduces Ca2+ permeation through NMDARs.
Fig. 6: EU1622-14 modulates Na+ and Ca2+ influx through NMDARs in a biased manner.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Code availability

The code that support the analysis of the findings contained in this study are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors thank K. Ogden for help with analytical software development and Y. Du and the Emory Chemical Biology Discovery Center for their invaluable assistance. This work was supported by the NINDS (NS065371 and NS111619, to S.F.T.), NICHD (HD082373, to H.Y.), NIMH (MH109026, to G.B.), Citizens United for Research in Epilepsy (to S.A.S.) and the Emory University Research Committee (to S.A.S.).

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The authors contributed in the following manner: conceptualization (S.F.T., R.E.P. and S.A.S.); data curation and formal analysis (R.E.P., S.A.S., C.S., A.K., G.F.-C., H.Y. and S.F.T.); funding acquisition (S.A.S., S.F.T., H.Y., D.C.L. and G.J.B.); investigation (R.E.P., S.A.S., C.S., A.K., J.Z., P.L., E.G.-A., G.F.-C., M.P.E., D.S.M. and P.B.); development or design of methodology (R.E.P., S.A.S., S.F.T., E.G.-A., G.F.-C., M.P.E., G.J.B., D.S.M., D.C.L. and L.S.L.); project administration (R.E.P., S.F.T. and S.A.S.); provision of reagents, materials and analysis tools (P.K.R.G., E.G.-A., G.F.-C., P.B., G.J.B., M.P.E., D.S.M., D.C.L. and L.S.L.); software (R.E.P. and S.F.T.); supervision (S.F.T., L.S.L., D.C.L. and G.J.B.); verification (R.E.P., S.A.S., C.S., A.K., G.F.-C., M.P.E. and D.S.M.); and visualization and writing (all authors).

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Correspondence to Stephen F. Traynelis.

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Competing interests

Several authors have competing interests. S.F.T. is a consultant for Janssen Pharmaceuticals, principal investigator on research grants from Janssen and Allergan to Emory University School of Medicine, a member of the scientific advisory board for Sage Therapeutics, the GRIN2B Foundation, and the CureGRIN Foundation, co-founder of NeurOp and receives royalties for software. D.C.L. is a member of the Board of Directors for NeurOp. D.C.L., D.S.M., E.G.A., G.F.C., P.K.R.G., L.S.L., M.P.E., S.F.T. are co-inventors on Emory-owned intellectual property that includes allosteric modulators of NMDA receptor function. H.Y. is principal investigator on a research grant from Sage Therapeutics to Emory University School of Medicine.

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Perszyk, R.E., Swanger, S.A., Shelley, C. et al. Biased modulators of NMDA receptors control channel opening and ion selectivity. Nat Chem Biol 16, 188–196 (2020). https://doi.org/10.1038/s41589-019-0449-5

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