Structural basis for cannabinoid-induced potentiation of alpha1-glycine receptors in lipid nanodiscs

Arvind Kumar, Kayla Kindig, Shanlin Rao, Afroditi-Maria Zaki, Sandip Basak, Mark S. P. Sansom, Philip C. Biggin and Sudha Chakrapani ()
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Arvind Kumar: Case Western Reserve University
Kayla Kindig: Case Western Reserve University
Shanlin Rao: University of Oxford
Afroditi-Maria Zaki: University of Oxford
Sandip Basak: Case Western Reserve University
Mark S. P. Sansom: University of Oxford
Philip C. Biggin: University of Oxford
Sudha Chakrapani: Case Western Reserve University

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract Nociception and motor coordination are critically governed by glycine receptor (GlyR) function at inhibitory synapses. Consequentially, GlyRs are attractive targets in the management of chronic pain and in the treatment of several neurological disorders. High-resolution mechanistic details of GlyR function and its modulation are just emerging. While it has been known that cannabinoids such as Δ9-tetrahydrocannabinol (THC), the principal psychoactive constituent in marijuana, potentiate GlyR in the therapeutically relevant concentration range, the molecular mechanism underlying this effect is still not understood. Here, we present Cryo-EM structures of full-length GlyR reconstituted into lipid nanodisc in complex with THC under varying concentrations of glycine. The GlyR-THC complexes are captured in multiple conformational states that reveal the basis for THC-mediated potentiation, manifested as different extents of opening at the level of the channel pore. Taken together, these structural findings, combined with molecular dynamics simulations and functional analysis, provide insights into the potential THC binding site and the allosteric coupling to the channel pore.

Date: 2022
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DOI: 10.1038/s41467-022-32594-5

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