NDLI: Molecular Determinants of Subtype-selective Efficacies of Cytisine and the Novel Compound NS3861 at Heteromeric Nicotinic Acetylcholine Receptors

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Molecular Determinants of Subtype-selective Efficacies of Cytisine and the Novel Compound NS3861 at Heteromeric Nicotinic Acetylcholine Receptors

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Molecular Determinants of Subtype-selective Efficacies of Cytisine and the Novel Compound NS3861 at Heteromeric Nicotinic Acetylcholine Receptors

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Balle, Thomas Timmermann, Daniel B. Gajhede, Michael Ahring, Philip K. Kastrup, Jette S. Harpsøe, Kasper Dyhring, Tino Jensen, Marianne L. Nielsen, Elsebet Ø. Hald, Helle Peters, Dan
Description	Author Affiliation: Harpsøe K ( Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.)
Abstract	Deciphering which specific agonist-receptor interactions affect efficacy levels is of high importance, because this will ultimately aid in designing selective drugs. The novel compound NS3861 and cytisine are agonists of nicotinic acetylcholine receptors (nAChRs) and both bind with high affinity to heteromeric 3ß4 and 4ß2 nAChRs. However, initial data revealed that the activation patterns of the two compounds show very distinct maximal efficacy readouts at various heteromeric nAChRs. To investigate the molecular determinants behind these observations, we performed in-depth patch clamp electrophysiological measurements of efficacy levels at heteromeric combinations of 3- and 4-, with ß2- and ß4-subunits, and various chimeric constructs thereof. Compared with cytisine, which selectively activates receptors containing ß4- but not ß2-subunits, NS3861 displays the opposite ß-subunit preference and a complete lack of activation at 4-containing receptors. The maximal efficacy of NS3861 appeared solely dependent on the nature of the ligand-binding domain, whereas efficacy of cytisine was additionally affected by the nature of the ß-subunit transmembrane domain. Molecular docking to nAChR subtype homology models suggests agonist specific interactions to two different residues on the complementary subunits as responsible for the ß-subunit preference of both compounds. Furthermore, a principal subunit serine to threonine substitution may explain the lack of NS3861 activation at 4-containing receptors. In conclusion, our results are consistent with a hypothesis where agonist interactions with the principal subunit ( ) primarily determine binding affinity, whereas interactions with key amino acids at the complementary subunit (ß) affect agonist efficacy.
ISSN	00219258
e-ISSN	1083351X
Journal	Journal of Biological Chemistry
Issue Number	4
Volume Number	288
Language	English
Publisher	American Society for Biochemistry and Molecular Biology (United States)
Publisher Date	2013-01-25
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Alkaloids Pharmacology Azabicyclo Compounds Receptors, Nicotinic Metabolism Thiophenes Animals Azocines Cloning, Molecular Dose-Response Relationship, Drug Drug Design Electrophysiology HEK293 Cells Ligands Models, Chemical Oocytes Patch-Clamp Techniques Protein Conformation Protein Structure, Tertiary Quinolizines Chemistry Xenopus Laevis Research Support, Non-U.S. Gov't Biochemistry Molecular Biology
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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