Allosteric activation of the 5-HT_3AB receptor by mCPBG
The 5-HT_3AB receptor contains three A and two B subunits in an A-A-B-A-B order. However, serotonin function at the 5-HT_3AB receptor has been shown to depend solely on the A-A interface present in the homomeric receptor. Using mutations at sites on both the primary (E122) and complementary (Y146) faces of the B subunit, we demonstrate that meta-chlorophenyl biguanide (mCPBG), a 5-HT_3 selective agonist, is capable of binding to and activating the 5-HT_3AB receptor at all five subunit interfaces of the heteromer. Further, mCPBG is capable of allosterically modulating the activity of serotonin from these sites. While these five binding sites are similar enough that they form to a monophasic dose – response relationship, we uncover subtle differences in the heteromeric binding sites. We also find that the A-A interface appears to contribute disproportionately to the efficacy of 5-HT_3AB receptor activation.
© 2014 Published by Elsevier Ltd. Received 8 July 2014. Received in revised form 16 October 2014. Accepted 10 December 2014. Available online 23 December 2014. We would like to thank Dr. Sarah Lummis (Cambridge) and Dr. Noah Duffy for helpful discussion. This work was supported by the NIH (NS 34407).
Accepted Version - nihms651345.pdf