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.
🔬 Techniques
🔭 Microscopes
✨ Fluorophores
🧪 Sample Preparation
🔬 Cell Lines
🏭 Microscope Brands
🏛️ Research Organizations (ROR)
Affiliated research institutions:
📊 Figures
Figure 1.
Screen of mutant u03b17 nAChR LBD ion channel activity against clinically used drugs. A) Schematic of modular PSAM-IPD chimeric channels for cell activation and inhibition. B) Screen of 41 u03b17u2013...
Figure 2.
Development of an ultrapotent PSAM for varenicline. A) Varenicline (left) and tropisetron (right) bind AChBPs in distinct orientations. Dashed line: H-bond with Trp 147 . Parentheses: homologous u03b1...
Figure 3.
PSAM 4 -GlyR neuron silencing in mice and a monkey. A) PSAM 4 -GlyRu2014IRESu2014EGFP targeted unilaterally to the SNr. Inset: schematic of unilateral SNr transduction and contralateral rotation. Aste...
Figure 4.
Highly selective chemogenetic agonists. A) Synthetic pathways (letters) for uPSEM agonists (see Methods). B) Comparison of uPSEM agonist EC50s at PSAM 4 channels and endogenous varenicline targets, as...
Figure 5.
Neuron silencing with uPSEMs and PSAM 4 -GlyR in vivo . (A) Experimental design for monitoring hippocampal CA1 neuron silencing with PSAM 4 -GlyR and uPSEM 792 using in vivo two photon Ca 2+ imaging i...
Figure images are served from the NIH/NLM PubMed Central Open Access Subset or Europe PMC; copyright remains with the publishers and authors.
💬 Discussion
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