Diverse arrestin-recruiting and endocytic profiles of tricyclic antipsychotics acting as direct α2A adrenergic receptor ligands

NEUROPHARMACOLOGY

卷:116

Article

Cottingham, Christopher^1,4  Che, Pulin¹  Zhang, Wei⁵  Wang, Hongxia¹  Wang, Raymond X.²  Percival, Stefanie¹  Birky, Tana¹  Zhou, Lufang²  Jiao, Kai³  Wang, Qin¹ 

[1] Univ Alabama Birmingham, Dept Cell Mol & Dev Biol, Birmingham, AL 35294 USA

[2] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA

[3] Univ Alabama Birmingham, Dept Genet, Birmingham, AL 35294 USA

[4] Morehead State Univ, Dept Biol & Chem, Morehead, KY 40351 USA

[5] Southern Res Inst, Birmingham, AL 35205 USA

关键词: Antipsychotic;    Endocytosis;    Arrestin;    Biased agonism;    alpha(2) adrenergic receptor;    Lipid raft;   

DOI  :  10.1016/j.neuropharm.2016.12.004

来源: Elsevier

【 摘 要 】

The therapeutic mechanism of action underlying many psychopharmacological agents remains poorly understood, due largely to the extreme molecular promiscuity exhibited by these agents with respect to potential central nervous system targets. Agents of the tricyclic chemical class, including both antidepressants and antipsychotics, exhibit a particularly high degree of molecular promiscuity; therefore, any clarification of how these agents interact with specific central nervous system targets is of great potential significance to the field. Here, we present evidence demonstrating that tricyclic antipsychotics appear to segregate into three distinct groups based upon their molecular interactions with the centrally important alpha(2A) adrenergic receptor (AR). Specifically, while the alpha(2A)AR binds all antipsychotics tested with similar affinities, and none of the agents are able to induce classical heterotrimeric G protein-mediated alpha(2A)AR signaling, significant differences are observed with respect to arrestin3 recruitment and receptor endocytosis. All antipsychotics tested induce arrestin3 recruitment to the alpha(2A)AR, but with differing strengths. Both chlorpromazine and clozapine drive significant alpha(2A)AR endocytosis, but via differing clathrin-dependent and lipid raft-dependent pathways, while fluphenazine does not drive a robust response. Intriguingly, in silico molecular modeling suggests that each of the three exhibits unique characteristics in interacting with the alpha(2A)AR ligand-binding pocket. In addition to establishing these three antipsychotics as novel arrestin-biased ligands at the alpha(2A)AR, our findings provide key insights into the molecular actions of these clinically-important agents. (C) 2016 Elsevier Ltd. All rights reserved.

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