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The small molecule CLP257 does not modify activity of the K+–Cl− co-transporter KCC2 but does potentiate GABAA receptor activity

Nature Medicine volume 23, pages 1394–1396 (2017)Cite this article

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To the Editor:

The neuronal K+–Cl− co-transporter KCC2 (also known as solute carrier family 12 member 5, or SLC12A5) critically maintains the neuronal Cl− gradient to establish hyperpolarizing signaling by GABAA receptors, the primary mediators of fast synaptic inhibition in the brain. These receptors are also the principal targets of benzodiazepines, neurosteroids, and intravenous general anesthetics1. The downregulation of KCC2 in neuropathic pain models and seizure-related disorders indentifies it as a putative therapeutic target. Through a small-molecule screen in neuroblastoma/glioma-derivative NG108-15 cells, Gagnon et al.2 identified CLP257 as a 'KCC2 activator'. We therefore sought to confirm and further determine its mechanism of action.

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Figure 1: CLP257 does not affect KCC2 function.

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Acknowledgements

We would like to thank S. Geschwindner for critical comments and discussion on the manuscript. We would like to thank G.J. Augustine (Korea Institute of Science and Technology) for generously providing the SuperClomeleon construct. This work was supported by funding from AstraZeneca, a grant from the Simons Foundation (206026 to S.J.M.), NIH–NINDS grants NS051195, NS056359, NS081735, and NS087662 (S.J.M.), and NIH–NIMH MH097446 (P.A.D.).

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Author notes

  1. Ross A Cardarelli, Karen Jones and Lucie I Pisella: These authors contributed equally to this work.

Authors and Affiliations

  1. AstraZeneca Tufts Laboratory for Basic and Translational Neuroscience, Boston, Massachusetts, USA

    Ross A Cardarelli, Heike J Wobst, Liliya Silayeva, Qi Wang, Nicholas J Brandon, Tarek Z Deeb & Stephen J Moss

  2. Discovery Sciences, IMED Biotech Unit, AstraZeneca, Alderley Park, UK

    Karen Jones, Paul M Sharpe & Matthew P Burnham

  3. INMED, INSERM, Unité 901, Marseille, France

    Lucie I Pisella, Ilona Chudotvorova, Justine Guyot & Igor Medina

  4. Aix–Marseille Université, UMR 901, Marseille, France

    Lucie I Pisella, Ilona Chudotvorova, Justine Guyot & Igor Medina

  5. Neuroscience, IMED Biotech Unit, AstraZeneca, Boston, Massachusetts, USA

    Heike J Wobst, Stephen Zicha, Jörg Holenz, Mark E Duggan, John Dunlop, Robert J Mather, Qi Wang & Nicholas J Brandon

  6. Discovery Sciences, IMED Biotech Unit, AstraZeneca, Cambridge, UK

    Lisa J McWilliams & David J Baker

  7. Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts, USA

    Danielle H Morrow, Paul A Davies & Stephen J Moss

  8. Discovery Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden

    Niek Dekker

  9. Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK

    Stephen J Moss

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Contributions

R.A.C., T.Z.D., I.M., P.A.D., S.Z., J.D., R.J.M., N.J.B., and S.J.M. designed experiments. R.A.C., K.J., L.I.P., H.J.W., L.J.M., D.J.B., I.C., J.G., L.S., and T.Z.D. performed all the experiments and subsequent analysis. P.M.S., M.P.B., D.H.M., N.D., J.H., M.E.D., R.J.M., and Q.W. produced all reagents or oversaw production of reagents. R.A.C., T.Z.D., I.M., N.J.B., and S.J.M. wrote the manuscript.

Corresponding authors

Correspondence to Nicholas J Brandon, Tarek Z Deeb or Stephen J Moss.

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Competing interests

K.J., L.J.M., P.M.S., M.P.B., D.J.B., N.D., R.J.M., S.Z., Q.W., J.H., M.E.D., J.D., and N.J.B. are or were full-time employees and shareholders of AstraZeneca. S.J.M. serves as a consultant for SAGE therapeutics and AstraZeneca; these relationships are regulated by Tufts University.

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Cardarelli, R., Jones, K., Pisella, L. et al. The small molecule CLP257 does not modify activity of the K+–Cl− co-transporter KCC2 but does potentiate GABAA receptor activity. Nat Med 23, 1394–1396 (2017). https://doi.org/10.1038/nm.4442

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