Dual Antagonism of α9α10 nAChR and GABA<sub>B</sub> Receptor-Coupled Ca<sub>V</sub>2.2 Channels by an Analgesic αO-Conotoxin Analogue
Xiao Li, Han‐Shen Tae, Shen Chen, Arsalan Yousuf, Linhong Huang, Jinghui Zhang, Tao Jiang, David J. Adams, Rilei Yu
Abstract
Pain severely affects the physical and mental health of patients. The need to develop nonopioid analgesic drugs to meet medical demands is urgent. In this study, we designed a truncated analogue of αO-conotoxin, named GeX-2, based on disulfide-bond deletion and sequence truncation. GeX-2 retained the potency of its parent peptide at the human α9α10 nAChR and exhibited potent inhibitory activity at Ca V 2.2 channels via activation of the GABA B receptor (GABA B R). Importantly, GeX-2 significantly alleviated pain in the rat model of chronic constriction injury. The dual inhibition of GeX-2 at both α9α10 nAChRs and Ca V 2.2 channels is speculated to synergistically mediate the potent analgesic effects. Results from site-directed mutagenesis assay and computational modeling suggest that GeX-2 preferentially interacts with the α10(+)α10(−) binding site of α9α10 nAChR and favorably binds to the top region of the GABA B R2 subunit. The study offers vital insights into the molecular action mechanism of GeX-2, demonstrating its potential as a novel nonopioid analgesic.