TY - JOUR
T1 - Ligand-directed serotonin 5-HT2C receptor desensitization and sensitization
AU - Felsing, Daniel E.
AU - Canal, Clinton E.
AU - Booth, Raymond G.
N1 - Funding Information:
Drs. Myong Sang Kim, Rajeev Sakhuja, and Zhuming Sun synthesized the PAT compounds, Dr. John Allen determined expression level of 5-HT 2C receptors in U2OS cells, and Dr. David Janero, Charles Perry, Caitlin Schlagal helped edit the manuscript. These studies were funded by grants from the National Institute of Mental Health and National Institute on Drug Abuse ( RO1MH081193 , RO1DA030989 , R21DA040907 ), and the Department of Defense (CDMRP PR141869 , AR160095 ). The NIMH, NIDA, and DOD did not have a role in study design, data collection, analysis, and interpretation, writing the manuscript, or in the decision to submit the paper for publication.
Publisher Copyright:
© 2019 Elsevier B.V.
PY - 2019/4/5
Y1 - 2019/4/5
N2 - 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-HT2C GPCRs is pharmacotherapeutic for obesity, but there is tolerance to the anorectic effect of the only approved 5-HT2C agonist, lorcaserin. We tested the hypothesis that different agonists or inverse agonists differentially desensitize or sensitize, respectively, canonical 5-HT2C-mediated activation of phospholipase C (PLC) signaling in vitro. Lorcaserin, which displays potency and efficacy equal to 5-HT, desensitized the 5-HT2C 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-HT2C 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-HT2C-PLC signaling. Several 5-HT2C 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-HT2C-PLC signaling. We observed robust positive correlations between the magnitude of 5-HT2C desensitization and agonist efficacy to stimulate PLC or to recruit β-arrestin. In contrast, different inverse agonists caused different magnitudes of 5-HT2C sensitization that did not correlate with efficacy (or potency) to inhibit constitutive 5-HT2C-PLC signaling. Assessment of the 5-HT2C-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-HT2C desensitization and sensitization processes.
AB - 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-HT2C GPCRs is pharmacotherapeutic for obesity, but there is tolerance to the anorectic effect of the only approved 5-HT2C agonist, lorcaserin. We tested the hypothesis that different agonists or inverse agonists differentially desensitize or sensitize, respectively, canonical 5-HT2C-mediated activation of phospholipase C (PLC) signaling in vitro. Lorcaserin, which displays potency and efficacy equal to 5-HT, desensitized the 5-HT2C 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-HT2C 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-HT2C-PLC signaling. Several 5-HT2C 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-HT2C-PLC signaling. We observed robust positive correlations between the magnitude of 5-HT2C desensitization and agonist efficacy to stimulate PLC or to recruit β-arrestin. In contrast, different inverse agonists caused different magnitudes of 5-HT2C sensitization that did not correlate with efficacy (or potency) to inhibit constitutive 5-HT2C-PLC signaling. Assessment of the 5-HT2C-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-HT2C desensitization and sensitization processes.
KW - 5-HT receptor
KW - Aminotetralin
KW - Desensitization
KW - Sensitization
KW - phospholipase C
KW - β-arrestin
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U2 - 10.1016/j.ejphar.2019.01.037
DO - 10.1016/j.ejphar.2019.01.037
M3 - Article
C2 - 30689993
AN - SCOPUS:85061227611
SN - 0014-2999
VL - 848
SP - 131
EP - 139
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
ER -