High-frequency HTR3B variant associated with major depression dramatically augments the signaling of the human 5-HT3AB receptor
Department of Medicinal Chemistry; Program in Neuroscience
Life Sciences | Medicine and Health Sciences
The 5-hydroxytryptamine-3 (5-HT3) receptor mediates the fast excitatory neurotransmission of serotonin and is known to mediate the nausea/emesis induced by radio/chemotherapy and anesthetics. A polymorphism encoding the variation Y129S in the 5-HT3B subunit exists in high frequency in the general population and has been shown to be inversely correlated to the incidence of major depression in women. We show that 5-HT3AB(Y129S) receptors exhibit a substantially increased maximal response to serotonin compared with WT receptors in two fluorescence-based cellular assays. In electrophysiological recordings, the deactivation and desensitization kinetics of the 5-HT3AB(Y129S) receptor are 20- and 10-fold slower, respectively, than those of the WT receptor. Single-channel measurements reveal a 7-fold-increased mean open time of 5-HT3AB(Y129S) receptors compared with WT receptors. The augmented signaling displayed by 5-HT3AB(Y129S) receptors may confer protection against the development of depression. The variant also may influence the development and/or treatment of nausea and other disorders involving 5-HT3 receptors. Thus, the impact of the high-frequency variant 5-HT3B(Y129S) on 5-HT3AB receptor signaling calls for a search for additional phenotypes, and the variant may thus aid in establishing the role of the 5-HT3AB receptor in pathophysiology.
DOI of Published Version
Proc Natl Acad Sci U S A. 2008 Jan 15;105(2):722-7. Epub 2008 Jan 9. Link to article on publisher's site
Proceedings of the National Academy of Sciences of the United States of America
Krzywkowski, Karen; Davies, Paul A.; Feinberg-Zadek, Paula Leslie; Brauner-Osborne, Hans; and Jensen, Anders A., "High-frequency HTR3B variant associated with major depression dramatically augments the signaling of the human 5-HT3AB receptor" (2008). GSBS Student Publications. 1429.