TY - JOUR
T1 - Comparative exploration of the structure–activity space of cloned a-like octopamine receptors from a marine and a terrestrial arthropods
AU - Dalwadi, Dhwanil A.
AU - Schetz, John A.
N1 - Funding Information:
This work was supported in part by grants from the Office of Naval Research [Grants N00014-08-1-0094 and N00014-12-M-0062]; the National Science Foundation [Grant 1248681]; a contract from Animal Biotech LLC, Dallas, Texas, USA; and institutional funds G67673. https://doi.org/10.1124/mol.117.108456. The authors thank Dr. Ulrika Lind, Department of Marine Sciences, University of Gothenburg, Goteborg, Sweden and Dr. Ronald L. Davis, Department of Neuroscience, The Scripps Research Institute, Jupiter, Florida for generously providing the BiOctR and DmOctR sequences, respectively, and Dr. Myron Toews, Department of Pharmacology & Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska for generously providing HEK293 cells stably expressing the human a2C adrenergic receptor.
Publisher Copyright:
Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics
PY - 2017/9
Y1 - 2017/9
N2 - The a-like octopamine receptors (OctR) are believed to be the evolutionary precursor to the vertebrate a2-adrenergic receptors (a2-ARs) based upon sequence similarity and the ability to interact with norepinephrine and a number of compounds that bind with high affinity to a2-ARs. Barnacles and fruit flies are two prominent model marine and terrestrial representatives of the Arthropoda phylum, and although a-like OctRs have been cloned from Balanus improvisus (BiOctR) and Drosophila melanogaster (DmOctR), little is known about the structure–activity space for these important species. A diverse panel of 22 probes spanning different structural classes were employed to interrogate the structure–activity of the BiOctR and DmOctR. While BiOctR and DmOctR exhibited similar functional profiles for mammalian biogenic amine G protein–coupled receptor agonists and antagonists, some ligands had dramatically different mechanisms of action. For instance, significant differences in the efficacy for some agonists were observed, including that vertebrate biogenic amines structurally related to octopamine acted as superagonists at the DmOctR but partial agonists at the BiOctR, and the two species diverged in their sensitivities to the a2-AR antagonist [3H]rauwolscine. Furthermore, sodium enhanced [3H]rauwolscine’s interactions with the BiOctR, but not at a vertebrate a2-AR. Molecular mechanistic studies indicate that rauwolscine interacts with the BiOctR, DmOctR, and a2C-adrenergic receptor at an allosteric site. In addition, compounds that acted as agonists at a cloned a-like BiOctR also induced a hyperactivity response in Balanus cyprids mediated by the a-like OctR, suggesting that the receptor may serve as a higher throughput proxy for discovering compounds with potential cyprid deterrent properties.
AB - The a-like octopamine receptors (OctR) are believed to be the evolutionary precursor to the vertebrate a2-adrenergic receptors (a2-ARs) based upon sequence similarity and the ability to interact with norepinephrine and a number of compounds that bind with high affinity to a2-ARs. Barnacles and fruit flies are two prominent model marine and terrestrial representatives of the Arthropoda phylum, and although a-like OctRs have been cloned from Balanus improvisus (BiOctR) and Drosophila melanogaster (DmOctR), little is known about the structure–activity space for these important species. A diverse panel of 22 probes spanning different structural classes were employed to interrogate the structure–activity of the BiOctR and DmOctR. While BiOctR and DmOctR exhibited similar functional profiles for mammalian biogenic amine G protein–coupled receptor agonists and antagonists, some ligands had dramatically different mechanisms of action. For instance, significant differences in the efficacy for some agonists were observed, including that vertebrate biogenic amines structurally related to octopamine acted as superagonists at the DmOctR but partial agonists at the BiOctR, and the two species diverged in their sensitivities to the a2-AR antagonist [3H]rauwolscine. Furthermore, sodium enhanced [3H]rauwolscine’s interactions with the BiOctR, but not at a vertebrate a2-AR. Molecular mechanistic studies indicate that rauwolscine interacts with the BiOctR, DmOctR, and a2C-adrenergic receptor at an allosteric site. In addition, compounds that acted as agonists at a cloned a-like BiOctR also induced a hyperactivity response in Balanus cyprids mediated by the a-like OctR, suggesting that the receptor may serve as a higher throughput proxy for discovering compounds with potential cyprid deterrent properties.
UR - http://www.scopus.com/inward/record.url?scp=85026816409&partnerID=8YFLogxK
U2 - 10.1124/mol.117.108456
DO - 10.1124/mol.117.108456
M3 - Review article
C2 - 28663279
AN - SCOPUS:85026816409
SN - 0026-895X
VL - 92
SP - 297
EP - 309
JO - Molecular Pharmacology
JF - Molecular Pharmacology
IS - 3
ER -