A PHP Error was encountered

Severity: Warning

Message: file_get_contents(https://...@pubfacts.com&api_key=b8daa3ad693db53b1410957c26c9a51b4908&a=1): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests

Filename: helpers/my_audit_helper.php

Line Number: 176

Backtrace:

File: /var/www/html/application/helpers/my_audit_helper.php
Line: 176
Function: file_get_contents

File: /var/www/html/application/helpers/my_audit_helper.php
Line: 250
Function: simplexml_load_file_from_url

File: /var/www/html/application/helpers/my_audit_helper.php
Line: 3122
Function: getPubMedXML

File: /var/www/html/application/controllers/Detail.php
Line: 575
Function: pubMedSearch_Global

File: /var/www/html/application/controllers/Detail.php
Line: 489
Function: pubMedGetRelatedKeyword

File: /var/www/html/index.php
Line: 316
Function: require_once

A photoreactive analog of allopregnanolone enables identification of steroid-binding sites in a nicotinic acetylcholine receptor. | LitMetric

AI Article Synopsis

  • Neuroactive steroids like allopregnanolone and its analogs modulate ion channels, acting as positive allosteric modulators on GABA receptors and inhibitors on nicotinic acetylcholine receptors.
  • A novel compound, FNBzoxy-AP, was studied for its ability to bind to nAChRs and was found to be more potent than existing analogs like alphaxalone in inhibiting certain actions of these receptors.
  • Three unique binding sites for FNBzoxy-AP were identified on the nAChR, suggesting interactions in the ion channel and other areas, and indicating that steroid binding alters receptor states.

Article Abstract

Many neuroactive steroids potently and allosterically modulate pentameric ligand-gated ion channels, including GABA receptors (GABAR) and nicotinic acetylcholine receptors (nAChRs). Allopregnanolone and its synthetic analog alphaxalone are GABAR-positive allosteric modulators (PAMs), whereas alphaxalone and most neuroactive steroids are nAChR inhibitors. In this report, we used 11β-(-azidotetrafluorobenzoyloxy)allopregnanolone (FNBzoxy-AP), a general anesthetic and photoreactive allopregnanolone analog that is a potent GABAR PAM, to characterize steroid-binding sites in the αβγδ nAChR in its native membrane environment. We found that FNBzoxy-AP (IC = 31 μm) is 7-fold more potent than alphaxalone in inhibiting binding of the channel blocker [H]tenocyclidine to nAChRs in the desensitized state. At 300 μm, neither steroid inhibited binding of [H]tetracaine, a closed-state selective channel blocker, or of [H]acetylcholine. Photolabeling identified three distinct [H]FNBzoxy-AP-binding sites in the nAChR transmembrane domain: 1) in the ion channel, identified by photolabeling in the M2 helices of βVal-261 and δVal-269 (position M2-13'); 2) at the interface between the αM1 and αM4 helices, identified by photolabeling in αM1 (αCys-222/αLeu-223); and 3) at the lipid-protein interface involving γTrp-453 (M4), a residue photolabeled by small lipophilic probes and promegestone, a steroid nAChR antagonist. Photolabeling in the ion channel and αM1 was higher in the nAChR-desensitized state than in the resting state and inhibitable by promegestone. These results directly indicate a steroid-binding site in the nAChR ion channel and identify additional steroid-binding sites also occupied by other lipophilic nAChR antagonists.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6514614PMC
http://dx.doi.org/10.1074/jbc.RA118.007172DOI Listing

Publication Analysis

Top Keywords

steroid-binding sites
12
ion channel
12
nicotinic acetylcholine
8
neuroactive steroids
8
channel blocker
8
identified photolabeling
8
nachr
6
channel
5
photoreactive analog
4
analog allopregnanolone
4

Similar Publications

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!