INVESTIGADORES
BOUZAT Cecilia Beatriz
artículos
Título:
Differential Pharmacological Activity of JN403 between á7 and Muscle Nicotinic Acetylcholine Receptors
Autor/es:
ARIAS H; DE ROSA MARíA JOSé; BERGE, I.; FEUERBACH D; BOUZAT C
Revista:
BIOCHEMISTRY
Editorial:
AMER CHEMICAL SOC
Referencias:
Lugar: Washington; Año: 2013 vol. 52 p. 8480 - 8488
ISSN:
0006-2960
Resumen:
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.