Ligand-directed serotonin 5-HT receptor desensitization and sensitization.

Eur J Pharmacol

Center for Drug Discovery, Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, United States; Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, United States; Department of Medicinal Chemistry, University of Florida, Gainesville, FL 32610, United States. Electronic address:

Published: April 2019

Exposure of G protein-coupled receptors (GPCRs) to agonists can desensitize receptor signaling and lead to drug tolerance, whereas inverse agonists can sensitize signaling. For example, activation of serotonin 5-HT GPCRs is pharmacotherapeutic for obesity, but there is tolerance to the anorectic effect of the only approved 5-HT agonist, lorcaserin. We tested the hypothesis that different agonists or inverse agonists differentially desensitize or sensitize, respectively, canonical 5-HT-mediated activation of phospholipase C (PLC) signaling in vitro. Lorcaserin, which displays potency and efficacy equal to 5-HT, desensitized the 5-HT receptor significantly more than 5-HT (p<0.05). Agonist chemotypes such as 2-aminotetralins, with similar potency but lower efficacy than 5-HT, produced little 5-HT desensitization. The piperazine agonist 1-(3-chlorophenyl)piperazine (mCPP), with lower potency but similar efficacy as 5-HT, elicited desensitization indistinguishable from 5-HT, while the piperazine agonist aripiprazole, with lower potency and efficacy, did not desensitize 5-HT-PLC signaling. Several 5-HT agonists also were assessed for β-arrestin recruitment-lorcaserin was a 'super-agonist', but a 2-aminotetralin and aripiprazole had nil activity, suggesting they are biased towards 5-HT-PLC signaling. We observed robust positive correlations between the magnitude of 5-HT desensitization and agonist efficacy to stimulate PLC or to recruit β-arrestin. In contrast, different inverse agonists caused different magnitudes of 5-HT sensitization that did not correlate with efficacy (or potency) to inhibit constitutive 5-HT-PLC signaling.  Assessment of the 5-HT-S407A point-mutated receptor indicated this residue's involvement in ligand-dependent desensitization, but we did not observe a role for protein kinase C.These data show that ligand structure uniquely impacts 5-HT desensitization and sensitization processes..

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767919PMC
http://dx.doi.org/10.1016/j.ejphar.2019.01.037DOI Listing

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