A Novel alpha 2/alpha 4 Subtype-selective Positive Allosteric Modulator of Nicotinic Acetylcholine Receptors Acting from the C-tail of an alpha Subunit

作者：Wang Jingyi; Kuryatov Alexander; Jin Zhuang; Norleans Jack; Kamenecka Theodore M; Kenny Paul J; Lindstrom Jon^*

来源：Journal of Biological Chemistry, 2015, 290(48): 28834-28846.

DOI：10.1074/jbc.M115.676551

• drug development
• electrophysiology
• nicotinic acetylcholine receptors (nAChR)
• receptor desensitization
• receptor structure-function
• nicotine addition
• positive allosteric modulator

Positive allosteric modulators (PAMs) of nicotinic acetylcholine receptors (nAChR) are important therapeutic candidates as well as valuable research tools. We identified a novel type II PAM, (R)-7-bromo-N-(piperidin-3-yl)benzo[b]thiophene-2-carboxamide (Br-PBTC), which both increases activation and reactivates desensitized nAChRs. This compound increases acetylcholine-evoked responses of 2* and 4* nAChRs but is without effect on 3* or 6* nAChRs (* indicates the presence of other nAChR subunits). Br-BPTC acts from the C-terminal extracellular sequences of 4 subunits, which is also a PAM site for steroid hormone estrogens such as 17-estradiol. Br-PBTC is much more potent than estrogens. Like 17-estradiol, the non-steroid Br-PBTC only requires one 4 subunit to potentiate nAChR function, and its potentiation is stronger with more 4 subunits. This feature enables Br-BPTC to potentiate activation of (42)(62)3 but not (62)(2)3 nAChRs. Therefore, this compound is potentially useful in vivo for determining functions of different 6* nAChR subtypes. Besides activation, Br-BPTC affects desensitization of nAChRs induced by sustained exposure to agonists. After minutes of exposure to agonists, Br-PBTC reactivated short term desensitized nAChRs that have at least two 4 subunits but not those with only one. Three 4 subunits were required for Br-BPTC to reactivate long term desensitized nAChRs. These data suggest that higher PAM occupancy promotes channel opening more efficiently and overcomes short and long term desensitization. This C-terminal extracellular domain could be a target for developing subtype or state-selective drugs for nAChRs.

• 出版日期2015-11-27