GSBS Student Publications

Title

High-frequency HTR3B variant associated with major depression dramatically augments the signaling of the human 5-HT3AB receptor

UMMS Affiliation

Department of Medicinal Chemistry; Program in Neuroscience

Date

1-11-2008

Document Type

Article

Medical Subject Headings

Cell Line; Cell Membrane; DNA, Complementary; Depression; Electrophysiology; Female; *Genetic Variation; Humans; Ions; Kinetics; Polymorphism, Genetic; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Serotonin; Signal Transduction; Transfection

Disciplines

Life Sciences | Medicine and Health Sciences

Abstract

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.

Rights and Permissions

Citation: 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

Related Resources

Link to Article in PubMed

Journal Title

Proceedings of the National Academy of Sciences of the United States of America

PubMed ID

18184810