Differential Pharmacological Activity of JN403 between á7 and Muscle Nicotinic Acetylcholine Receptors

ARIAS H; DE ROSA MARíA JOSé; BERGE, I.; FEUERBACH D; BOUZAT C

BIOCHEMISTRY

AMER CHEMICAL SOC

Lugar: Washington; Año: 2013 vol. 52 p. 8480 - 8488

0006-2960

ABSTRACT: The differential action of the novel agonist 8 JN403 at neuronal ¥á7 and muscle nicotinic receptors (AChRs) 9 was explored by using a combination of functional and struc- 10 tural approaches. Single-channel recordings reveal that JN403 11 is a potent agonist of ¥á7 but a very low-efficacy agonist of 12 muscle AChRs. JN403 elicits detectable openings of ¥á7 and 13 muscle AChRs at concentrations ¡­1000-fold lower and ¡­20- 14 fold higher, respectively, than that for ACh. Single-channel 15 activity elicited by JN403 is very similar to that elicited by ACh 16 in ¥á7 but profoundly different in muscle AChRs, where openings are brief and infrequent and do not appear in clusters at any 17 concentration. JN403 elicits single-channel activity of muscle AChRs lacking the ¥å subunit, with opening events being more 18 frequent and prolonged than those of wild-type AChRs. This finding is in line with the molecular docking studies predicting that 19 JN403 may form a hydrogen bond required for potent activation at the ¥á−¥ä but not at the ¥á−¥å binding site. JN403 does not 20 elicit detectable Ca2+ influx in muscle AChRs but inhibits (¡¾)-epibatidine-elicited influx mainly by a noncompetitive mechanism. 21 Such inhibition is compatible with single-channel recordings revealing that JN403 produces open-channel blockade and early 22 termination of ACh-elicited clusters, and it is therefore also a potent desensitizing enhancer of muscle AChRs. The latter 23 mechanism is supported by the JN403-induced increase in the level of binding of [3H]cytisine and [3H]TCP to resting AChRs. 24 Elucidation of the differences in activity of JN403 between neuronal ¥á7 and muscle AChRs provides further insights into 25 mechanisms underlying selectivity for ¥á7 AChRs.