Functional α6β4 acetylcholine receptor expression enables pharmacological testing of nicotinic agonists with analgesic properties

The α6β4 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 α6β4 receptors in recombinant systems has precluded drug discovery. Here, genome-wide screening identified ac...

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Bibliographic Details
Published in:The Journal of clinical investigation 2020-11, Vol.130 (11), p.6158-6170
Main Authors: Knowland, Daniel, Gu, Shenyan, Eckert, 3rd, William A, Dawe, G Brent, Matta, Jose A, Limberis, James, Wickenden, Alan D, Bhattacharya, Anindya, Bredt, David S
Format: Article
Language:English
Subjects:
Acetylcholine receptors (nicotinic)
Analgesics
Animals
Biomedical research
Calcium channels
Calcium channels (voltage-gated)
Cholinergic Agonists - pharmacology
Cloning
Dorsal root ganglia
Drug discovery
Endoribonucleases - genetics
Endoribonucleases - metabolism
Gene Expression Regulation - drug effects
Genomes
HEK293 Cells
Humans
Membrane Glycoproteins - genetics
Membrane Glycoproteins - metabolism
Mice
Mice, Knockout
mRNA
Narcotics
Neuralgia
Nicotine
Opioid receptors
Pain
Protein folding
Protein-Serine-Threonine Kinases - genetics
Protein-Serine-Threonine Kinases - metabolism
Proteins
Rats
Receptors, Cholinergic - biosynthesis
Receptors, Cholinergic - genetics
RNA Splicing - drug effects
X-Box Binding Protein 1 - genetics
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Summary:The α6β4 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 α6β4 receptors in recombinant systems has precluded drug discovery. Here, genome-wide screening identified accessory proteins that enable reconstitution of human α6β4 nAChRs. BARP, an auxiliary subunit of voltage-dependent calcium channels, promoted α6β4 surface expression while IRE1α, an unfolded protein response sensor, enhanced α6β4 receptor assembly. Effects on α6β4 involve BARP's N-terminal region and IRE1α's splicing of XBP1 mRNA. Furthermore, clinical efficacy of nicotinic agents in relieving neuropathic pain best correlated with their activity on α6β4. Finally, BARP-knockout, but not NACHO-knockout mice lacked nicotine-induced antiallodynia, highlighting the functional importance of α6β4 in pain. These results identify roles for IRE1α and BARP in neurotransmitter receptor assembly and unlock drug discovery for the previously elusive α6β4 receptor.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI140311