TY - JOUR
T1 - Tricyclic antidepressants exhibit variable pharmacological profiles at the α2A adrenergic receptor
AU - Cottingham, Christopher
AU - Percival, Stefanie
AU - Birky, Tana
AU - Wang, Qin
N1 - Funding Information:
Our thanks to Dr. Robert J. Lefkowitz (Duke University) for generously providing the Arr2,3 −/− MEF cell line, to Drs. Kai Jiao (UAB) and Kurt Gibbs (Morehead State) for helpful discussions, and to Bethanny Glahn (Morehead State) for routine maintenance of cell lines. This work was supported by a National Institute of Mental Health Grant ( MH081917 ), NARSAD Independent Investigator Award (to QW) and a National Institute of General Medical Sciences Grant ( P20GM103436 ).
PY - 2014/8/29
Y1 - 2014/8/29
N2 - Antidepressant mechanisms of action remain shrouded in mystery, greatly hindering our ability to develop therapeutics which can fully treat patients suffering from depressive disorders. In an attempt to shed new light on this topic, we have undertaken a series of studies investigating actions of tricyclic antidepressant drugs (TCAs) at the α2A adrenergic receptor (AR), a centrally important receptor, dysregulation of which has been linked to depression. Our previous work established a particular TCA, desipramine, as an arrestin-biased α2AAR ligand driving receptor endocytosis and downregulation but not canonical heterotrimeric G protein-mediated signaling. The present work is aimed at broadening our understanding of how members of the TCA drug class act at the α2AAR, as we have selected the closely related but subtly different TCAs imipramine and amitriptyline for evaluation. Our data demonstrate that these drugs do also function as direct arrestin-biased α2AAR ligands. However, these data reveal differences in receptor affinity and in the extent/nature of arrestin recruitment to and endocytosis of α2AARs. Specifically, amitriptyline exhibits an approximately 14-fold stronger interaction with the receptor, is a weaker driver of arrestin recruitment, and preferentially recruits a different arrestin subtype. Extent of endocytosis is similar for all TCAs studied so far, and occurs in an arrestin-dependent manner, although imipramine uniquely retains a slight ability to drive α2AAR endocytosis in arrestin-null cells. These findings signify an important expansion of our mechanistic understanding of antidepressant pharmacology, and provide useful insights for future medicinal chemistry efforts.
AB - Antidepressant mechanisms of action remain shrouded in mystery, greatly hindering our ability to develop therapeutics which can fully treat patients suffering from depressive disorders. In an attempt to shed new light on this topic, we have undertaken a series of studies investigating actions of tricyclic antidepressant drugs (TCAs) at the α2A adrenergic receptor (AR), a centrally important receptor, dysregulation of which has been linked to depression. Our previous work established a particular TCA, desipramine, as an arrestin-biased α2AAR ligand driving receptor endocytosis and downregulation but not canonical heterotrimeric G protein-mediated signaling. The present work is aimed at broadening our understanding of how members of the TCA drug class act at the α2AAR, as we have selected the closely related but subtly different TCAs imipramine and amitriptyline for evaluation. Our data demonstrate that these drugs do also function as direct arrestin-biased α2AAR ligands. However, these data reveal differences in receptor affinity and in the extent/nature of arrestin recruitment to and endocytosis of α2AARs. Specifically, amitriptyline exhibits an approximately 14-fold stronger interaction with the receptor, is a weaker driver of arrestin recruitment, and preferentially recruits a different arrestin subtype. Extent of endocytosis is similar for all TCAs studied so far, and occurs in an arrestin-dependent manner, although imipramine uniquely retains a slight ability to drive α2AAR endocytosis in arrestin-null cells. These findings signify an important expansion of our mechanistic understanding of antidepressant pharmacology, and provide useful insights for future medicinal chemistry efforts.
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U2 - 10.1016/j.bbrc.2014.08.024
DO - 10.1016/j.bbrc.2014.08.024
M3 - Article
C2 - 25128275
AN - SCOPUS:84908380244
SN - 0006-291X
VL - 451
SP - 461
EP - 466
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 3
ER -