Functional ?6?4 acetylcholine receptor expression enables pharmacological testing of nicotinic agonists with analgesic properties.

ABSTRACT: The ?6?4 nicotinic acetylcholine receptor (nAChR) is enriched in dorsal root ganglia neurons and is an attractive non-opioid therapeutic target for pain. However, difficulty expressing human ?6?4 receptors in recombinant systems has precluded drug discovery. Here, genome-wide screening identified accessory proteins that enable reconstitution of human ?6?4 nAChRs. BARP, an auxiliary subunit of voltage-dependent calcium channels, promoted ?6?4 surface expression while IRE1?, an unfolded protein response sensor, enhanced ?6?4 receptor assembly. Effects on ?6?4 involve BARP's N-terminal region and IRE1?'s splicing of XBP1 mRNA. Furthermore, clinical efficacy of nicotinic agents in relieving neuropathic pain best correlated with their activity on ?6?4. Finally, BARP-knockout, but not NACHO-knockout mice lacked nicotine-induced antiallodynia, highlighting the functional importance of ?6?4 in pain. These results identify roles for IRE1? and BARP in neurotransmitter receptor assembly and unlock drug discovery for the previously elusive ?6?4 receptor.

SUBMITTER: Knowland D 

PROVIDER: S-EPMC7598046 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature