High-frequency HTR3B variant associated with major depression dramatically augments the signaling of the human 5-HT3AB receptor.
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.
Krzywkowski
Karen
K
Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
Davies
Paul A
PA
Feinberg-Zadek
Paula L
PL
Bräuner-Osborne
Hans
H
Jensen
Anders A
AA
D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D003863:Depression / Q000235:genetics*; D004594:Electrophysiology / Q000379:methods; D005260:Female; D014644:Genetic Variation; D006801:Humans; D007477:Ions; D007700:Kinetics; D011110:Polymorphism, Genetic; D011985:Receptors, Serotonin / Q000096:biosynthesis* / Q000235:genetics*; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism*; D012701:Serotonin / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection
D018076:DNA, Complementary; C509410:HTR3B protein, human; D007477:Ions; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D012701:Serotonin