Unorthodox Acetylcholine Binding Sites Formed by α5 and ß3 Accessory Subunits in α4ß2* Nicotinic Acetylcholine Receptors.
J Biol Chem
; 291(45): 23452-23463, 2016 Nov 04.
Article
em En
| MEDLINE
| ID: mdl-27645992
ABSTRACT
All nicotinic acetylcholine receptors (nAChRs) evolved from homomeric nAChRs in which all five subunits are involved in forming acetylcholine (ACh) binding sites at their interfaces. Heteromeric α4ß2* nAChRs typically have two ACh binding sites at α4/ß2 interfaces and a fifth accessory subunit surrounding the central cation channel. ß2 accessory subunits do not form ACh binding sites, but α4 accessory subunits do at the α4/α4 interface in (α4ß2)2α4 nAChRs. α5 and ß3 are closely related subunits that had been thought to act only as accessory subunits and not take part in forming ACh binding sites. The effect of agonists at various subunit interfaces was determined by blocking homologous sites at these interfaces using the thioreactive agent 2-((trimethylammonium)ethyl) methanethiosulfonate (MTSET). We found that α5/α4 and ß3/α4 interfaces formed ACh binding sites in (α4ß2)2α5 and (α4ß2)2ß3 nAChRs. The α4/α5 interface in (ß2α4)2α5 nAChRs also formed an ACh binding site. Blocking of these sites with MTSET reduced the maximal ACh evoked responses of these nAChRs by 30-50%. However, site-selective agonists NS9283 (for the α4/α4 site) and sazetidine-A (for the α4/ß2 site) did not act on the ACh sites formed by the α5/α4 or ß3/α4 interfaces. This suggests that unorthodox sites formed by α5 and ß3 subunits have unique ligand selectivity. Agonists or antagonists for these unorthodox sites might be selective and effective drugs for modulating nAChR function to treat nicotine addiction and other disorders.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Acetilcolina
/
Receptores Nicotínicos
Limite:
Animals
/
Humans
Idioma:
En
Revista:
J Biol Chem
Ano de publicação:
2016
Tipo de documento:
Article