| First Author | Knowland D | Year | 2020 |
| Journal | J Clin Invest | Volume | 130 |
| Issue | 11 | Pages | 6158-6170 |
| PubMed ID | 33074244 | Mgi Jnum | J:302601 |
| Mgi Id | MGI:6508720 | Doi | 10.1172/JCI140311 |
| Citation | Knowland D, et al. (2020) Functional alpha6beta4 acetylcholine receptor expression enables pharmacological testing of nicotinic agonists with analgesic properties. J Clin Invest 130(11):6158-6170 |
| abstractText | The alpha6beta4 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 alpha6beta4 receptors in recombinant systems has precluded drug discovery. Here, genome-wide screening identified accessory proteins that enable reconstitution of human alpha6beta4 nAChRs. BARP, an auxiliary subunit of voltage-dependent calcium channels, promoted alpha6beta4 surface expression while IRE1alpha, an unfolded protein response sensor, enhanced alpha6beta4 receptor assembly. Effects on alpha6beta4 involve BARP's N-terminal region and IRE1alpha's splicing of XBP1 mRNA. Furthermore, clinical efficacy of nicotinic agents in relieving neuropathic pain best correlated with their activity on alpha6beta4. Finally, BARP-knockout, but not NACHO-knockout mice lacked nicotine-induced antiallodynia, highlighting the functional importance of alpha6beta4 in pain. These results identify roles for IRE1alpha and BARP in neurotransmitter receptor assembly and unlock drug discovery for the previously elusive alpha6beta4 receptor. |
