絞り込み

16755

広告

Non-equivalent Ligand Selectivity of Agonist Sites in (α4β2)2α4 Nicotinic Acetylcholine Receptors: A Key Determinant of Agonist Efficacy.

著者 Mazzaferro S , Gasparri F , New K , Alcaino C , Faundez M , Vasquez PI , Vijayan R , Biggin PC , Bermudez I
J Biol Chem.2014 Jun 16 ; ():.
この記事をPubMed上で見るPubMedで表示
この記事をGoogle翻訳上で見る Google翻訳で開く

スターを付ける スターを付ける     (5view , 0users)

Full Text Sources

The α4β2 nicotinic acetylcholine receptor (nAChR) is the most abundant nAChR type in the brain, and this receptor type exists in alternate (α4β2)2α4 and (α4β2)2β2 forms, which are activated by agonists with strikingly differing efficacies. Recent breakthroughs have identified an additional operational agonist binding site in the (α4β2)2α4 nAChR that is responsible for the signature sensitivity of this receptor to activation by agonists, yet the structural mechanism determining agonist efficacy at this receptor type are not yet fully understood. In this study, we characterised the ligand selectivity of the individual agonist sites of the(α4β2)2α4 nAChR to determine whether differences in agonist selectivity influences agonist efficacy. Applying the substituted cysteine accessibility method to individual agonist sites in concatenated (α4β2)2α4 receptors, we determined the agonist selectivity of the agonist sites of the (α4β2)2α4 receptor. We show that a) accessibility of substituted cysteines to covalent modification by methanesulphonate reagent depends on the agonist site at which the modification occurs and b) that agonists such as sazetidine-A and TC-2559 are excluded from the site at the α4/α4 interface. Given that additional binding to the agonist site in the α4/α4 interface, increases ACh efficacy and that agonists excluded from the agonist site at the α4/α4 interface behave as partial agonists, we conclude that the ability to engage all agonist sites in (α4β2)2α4 nAChRs is a key determinant of agonist efficacy. The findings add another level of complexity to the structural mechanisms that govern agonist efficacy in heteromeric nAChRs and related ligand gated ion channels.
PMID: 24936069 [PubMed - as supplied by publisher]
印刷用ページを開く Endnote用テキストダウンロード