Histidine 6.55 is a major determinant of ligand-biased signaling in dopamine D2L receptor
Tschammer N, Bollinger S, Kenakin T, Gmeiner P (2011)
Publication Language: English
Publication Type: Journal article, Original article
Publication year: 2011
Journal
Original Authors: Tschammer N., Bollinger S., Kenakin T., Gmeiner P.
Publisher: American Society for Pharmacology and Experimental Therapeutics (ASPET)
Book Volume: 79
Pages Range: 575-585
Journal Issue: 3
Abstract
In our previous studies, we demonstrated that the mutation of His393 to alanine results in an increased affinity of 1,4-disubstituted phenylpiperazines to the dopamine D receptor. This change most likely accounts for the reduced steric hindrance in this part of the binding pocket. In this work, we investigated the role of the steric hindrance imposed by the residue His393 for the receptor activation modulated by 1,4-disubstituted aromatic piperidines/piperazines. Site-directed mutagenesis and ligand modifications were used to probe the structural basis of ligand efficacy. The operational model of agonism was used to quantify the ligand bias between the ability of compounds to inhibit cAMP accumulation and stimulate extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation. Whereas substantial ligand-biased signaling was observed for the D wild-type receptor, an overall increase in agonism was observed for the D H393A mutant without noteworthy functional selectivity. Targeted chemical modification of the phenylpiperazine moiety at the site of its interaction with the residue His393 led to the functionally selective ligand {3-[4-(2,3-dihydro-benzofuran-7-yl)-piperazin-1- yl]-propyl}-pyrazol[1,5-a]pyridine-3-carboxamide (FAUC350) that has distinct signaling profiles toward adenylyl cyclase and ERK1/2. FAUC350 behaves as an antagonist in the inhibition of cAMP accumulation and as a partial agonist in the stimulation of ERK1/2 phosphorylation (efficacy = 55%). Overall, the residue His393 and proximate molecular substructures of receptor ligands were identified to be crucial for multidimensional ligand efficacy. Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics.
Authors with CRIS profile
Nuska Tschammer
Lehrstuhl für Pharmazeutische Chemie
Peter Gmeiner
Lehrstuhl für Pharmazeutische Chemie
Additional Organisation(s)
Involved external institutions
United States (USA) (US)How to cite
APA:
Tschammer, N., Bollinger, S., Kenakin, T., & Gmeiner, P. (2011). Histidine 6.55 is a major determinant of ligand-biased signaling in dopamine D2L receptor. Molecular Pharmacology, 79(3), 575-585. https://doi.org/10.1124/mol.110.068106
MLA:
Tschammer, Nuska, et al. "Histidine 6.55 is a major determinant of ligand-biased signaling in dopamine D2L receptor." Molecular Pharmacology 79.3 (2011): 575-585.
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