Functional consequences of a rare human serotonergic 5-HT1A receptor variant

Merav Tauber, Yair Ben-Chaim

Research output: Contribution to journalArticlepeer-review


Serotonin (5-HT) plays a central role in various brain functions via the activation of a family of receptors, most of them G protein coupled receptors (GPCRs). 5-HT1A receptor, the most abundant 5-HT receptors, was implicated in many brain dysfunctions and is a major target for drug discovery. Several genetic polymorphisms within the 5-HT1A receptor gene were identified and linked to different conditions, including anxiety and depression. Here, we used Xenopus oocytes to examine the effects of one of the functional polymorphism, Arg220Leu, on the function of the receptor. We found that the mutated receptor shows normal activation of G protein and normal 5-HT binding. On the other hand, the mutated receptor shows impaired desensitization, probably due to impairment in activation of β arrestin-dependent pathway. Furthermore, while the 5-HT1A receptor was shown to exhibit voltage dependent activation by serotonin and by buspirone, the mutated receptor was voltage-independent. Our results suggest a pronounced effect of the mutation on the function of the 5-HT1A receptor and add to our understanding of the molecular mechanism of its voltage dependence. Moreover, the findings of this study may suggest a functional explanation for the possible link between this variant and brain pathologies.

Original languageEnglish
Article number1270726
JournalFrontiers in Pharmacology
StatePublished - 2023

Bibliographical note

Funding Information:
The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by Israel Science Foundation grant 606/15 and by an internal grant from the open university of Israel.

Publisher Copyright:
Copyright © 2023 Tauber and Ben-Chaim.


  • G protein coupled receptors
  • genetic variation
  • serotonin receptors
  • voltage dependence
  • Xenopus oocytes


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