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

Abstract

The authors are all full-time employees of Janssen Pharmaceutical Companies of Johnson and Johnson.

Proteins for increased surface expression of the α6β4 nicotinic acetylcholine receptor: nothing but good news?

“…The dorsal root ganglia (DRG) play a role in nociception and coexpress α6 and β4 mRNA (23). Consistent with the experiments performed in HEK293T cells, wild-type DRG neurons had greater α6β4 surface levels than BARP-KO neurons (17). Nicotine has an antiallodynic effect in rodent models of neuropathic pain (24).…”

“…The authors found no difference between nicotine's antiallodynia properties in NACHO-KO mice compared to wild-type mice, consistent with the paper's viewpoint that α6β4 is the nAChR that carries out nicotine's antiallodynia effects. Inhibition of α4β2 did not prevent nicotine-induced antiallodynia (17).…”

“…As a caution, we do not yet know of a nicotinic agonist that affects α6-containing AChRs more potently than α4-containing nAChRs. ABT-894, one of the synthetic ligands tested by Knowland et al, has the opposite selectivity, with higher agonist activity at α4-containing nAChRs (17). We can hope that enhanced α6β4 levels at the plasma membrane will enable experiments to find an α6β4-selective ligand, thus providing a compound to test the hypothesis that such drugs will become nonaddictive opioids.…”

“…one such subtype, the α6β2β3 nAChR (25). One therefore hopes that both Parkinson's disease and nicotine dependence may also soon benefit from the ability to screen a full collection of nAChRs (17).…”

“…The group at Janssen Pharmaceutical Companies of Johnson & Johnson has systematically been identifying chaperone proteins for nAChR expression over the past few years; happily, in this issue of the JCI, they now report a combination of proteins that yield good expression of wild-type α6β4 nAChRs in recombinant systems (17). The top two proteins that increased the nicotine-evoked Ca 2+ response in unbiased genome-wide cotransfection were sodium channel β-subunit-anchoring and -regulatory protein (BARP) and IRE1α, an unfolded protein response (UPR) sensor.…”