The C and E subunits of the serotonin 5-HT3 receptor subtly modulate electrical properties of the receptor

Nor Syafinaz Yaakob, Dan Thanh Nguyen, Betty Exintaris, Helen Ruth Irving

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Abstract

Serotonin type 3 (5-hydroxytrptamine-3, 5-HT3) receptors are ligand-gated cation channels present in both central and peripheral nervous systems. In humans there are five different subunits (A, B, C, D and E) of 5-HT3 receptors which can form homomeric or heteromeric receptors that may account for discrepancies in patient responses to treatments. The present study commences characterisation of the profiles of human 5-HT3 receptors containing C and/or E subunits. Recombinant 5-HT3 receptors were expressed transiently in HEK293T cells and expression was checked via immunocytochemistry staining against each epitope-tagged subunits. Functional characterisation of different combinations of 5-HT3 receptor complexes was studied via patch clamp whole cell recordings. In this study, increased current was seen in cells containing A and C subunits but only subtle changes were seen in the electrical properties of cells expressing A, AE, or ACE subunits in response to the ligand, 5-HT. Both di- and tri-heteromeric 5-HT3 receptors were significantly inhibited by the antagonists, ondansetron and palonosetron. Notably, palonosetron exerted stronger and more rapid inhibition on the 5-HT3 receptor ACE tri-heteromer compared to homomeric and di-heteromeric counterparts. This study demonstrated that the C and E subunits when assembled as simple or complex heteromeric 5-HT3 receptors may alter efficacies of 5-HT and clinically used antagonists such as ondansetron and palonosetron, and this in turn may have implications for patient responses to therapies.

Original languageEnglish
Pages (from-to)1701-1709
Number of pages9
JournalBiomedicine & Pharmacotherapy
Volume97
DOIs
Publication statusPublished - 1 Jan 2018

Keywords

  • HTR3C
  • HTR3E
  • Ligand-gated ion channel
  • Ondansetron
  • Palonosetron
  • Patch-clamp

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