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Author Notes:

Correspondence: sternsons@janelia.hhmi.org (S.M.S.)

Author contributions: Author contributions: C.M. performed ex vivo electrophysiology and SNr silencing behavioral experiments. P.L. developed and synthesized uPSEMs and performed dose response assays with C.M. M.R. made ion channel constructs. J.B., J.G., and M.M. performed PET imaging and radioligand displacement at PSAM4-GlyR and α7 nAChR. X.

H. and A.G. performed rhesus macaque experiments. R.Z. and J.B. performed in vivo calcium imaging. S.M.S. conceived the project, designed experiments, and wrote the paper with input from all the authors.

We thank Prof. Jon Lindstrom for providing stable cell lines expressing human α4β2 nAChR or α7 nAChR. Receptor counter-screening and associated Ki determinations were generously provided by the National Institute of Mental Health’s Psychoactive Drug Screening Program, Contract # HHSN-271–2013-00017-C (NIMH PDSP).

We are grateful for support from Janelia core facility staff; Sarah Lindo performed in utero electroporations.

Disclosures: S.M.S., C.J.M., and P.H.L. have pending patents on this technology and own stock in Redpin Therapeutics, LLC, which is a biotech company focusing on therapeutic applications of chemogenetics. S.M.S. is a cofounder and consultant for Redpin Therapeutics. M.M. is a cofounder and owns stock in Metis Laboratories, Inc.

Subjects:

Research Funding:

S.M.S., C.M., P.L., and M.R. were funded by HHMI. X.H. and A.G. was supported by grant NIH ORIP OD P51-OD011132 to the Yerkes National Primate Research Center.

J.B. was supported by the Alfred P. Sloan Foundation, Klingenstein-Simons Foundation, NIH NINDS 1R01 NS109362–01, and Whitehall Foundation. M.M. is funded through NIDA IRP (ZIA000069).

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • Nicotinic acetylcholine receptors
  • Smoking cessation
  • Partial agonists
  • In-vivo
  • Discriminative stimulus
  • Global pallidus
  • Whole blood
  • Varenicline
  • Alpha-4 beta-2
  • Neurons

Ultrapotent chemogenetics for research and potential clinical applications

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Journal Title:

Science

Volume:

Volume 364, Number 6436

Publisher:

, Pages 146-+

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Chemogenetics enables noninvasive chemical control over cell populations in behaving animals. However, existing small-molecule agonists show insufficient potency or selectivity. There is also a need for chemogenetic systems compatible with both research and human therapeutic applications. We developed a new ion channel–based platform for cell activation and silencing that is controlled by low doses of the smoking cessation drug varenicline. We then synthesized subnanomolar-potency agonists, called uPSEMs, with high selectivity for the chemogenetic receptors. uPSEMs and their receptors were characterized in brains of mice and a rhesus monkey by in vivo electrophysiology, calcium imaging, positron emission tomography, behavioral efficacy testing, and receptor counterscreening. This platform of receptors and selective ultrapotent agonists enables potential research and clinical applications of chemogenetics.

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© 2019 American Association for the Advancement of Science. All rights reserved.

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