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

Proceedings of the National Academy of Sciences of the United States of America
K KrzywkowskiAnders A Jensen

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 addi...Continue Reading

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Citations

May 14, 2008·The Journal of Biological Chemistry·Matthew R LiveseyJohn A Peters
Nov 15, 2008·Pharmacogenetics and Genomics·Karen KrzywkowskiAnders A Jensen
Sep 11, 2009·Pharmacogenetics and Genomics·Christian HammerBeate Niesler
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Nov 19, 2013·PloS One·Emilia Horjales-AraujoLene Vase
May 10, 2008·Pharmacogenomics·Beate NieslerGudrun Rappold
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Jul 14, 2010·Pharmacology & Therapeutics·Jutta WalstabBeate Niesler
Mar 16, 2016·Neuroscience and Biobehavioral Reviews·Deepali GuptaMahesh Radhakrishnan
Nov 18, 2008·Journal of Neurochemistry·Joanna D HolbrookMartin J Gunthorpe
Mar 8, 2013·Journal of Clinical Pharmacy and Therapeutics·Xiao-Xu MaXiang-Ming Fang
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Aug 20, 2019·The European Journal of Neuroscience·Jochen WintererCsaba Földy
May 8, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Nawid MadjrohAnders A Jensen

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