Human 5-HT3B -- Tyr 129

Species Original Mutated to Mutation
Human Tyr 129 Ser

Y129S

Rat Equivalent Ser 125    
Mouse Equivalent Ser 125  

 

 

 

mTyr129Ser

Mutation in the human 5-HT3B receptor residue Y129S is a high frequency polymorphism, studied in transfected HEK cells. The Y129S mutation was reported to be associated with the incidence of major depression in women and the incidence and severity of nausea after paroxetine treatment of psychiatric patients.

The mutant 5-HT3B Y129S receptors exhibited increased maximal response to 5-HT compared with wild type receptors. In electrophysiological recordings, the deactivation and desensitization kinetics of the 5-HT3A/B (Y129S) receptor following activation by 5-HT were slower than those of wild type receptors, with an increased single channel mean open time in the mutant. The presence of the 5-HT3B Y129S subunit does not alter cell surface levels of functional 5-HT3A/B receptors. Mutating the 129 residue to different amino acid residues showed that all of the 10 amino acids tested enhanced 5HT3A/B receptor signaling.

 

Krzywkowski K, Davies PA, Feinberg-Zadek PL, Bräuner-Osborne H, Jensen AA. (2008) High-frequency HTR3B variant associated with major depression dramatically augments the signaling of the human 5-HT3AB receptor. Procedings of the National Academy of Sciences of the United States of America. 105(2):722-7

 

The 5-HT3B Y129S mutant, a common polymorphism with high frequency for the minor allele, decreased 5-HT3A/B receptor surface expression levels. This mutation is reportedly associated with the incidence of major depression in women, and of paroxetine-induced nausea The Y129S mutation has also been associated with bipolar affective disorder. The mutant 5-HT3B Y129S maximum 5-HT response measured using Ca(^2+) was three times greater than the response in wild type receptors with a maximum binding increase of only 17%. [see previous entry for possible causes of increased efficacy]

 

Walstab J, Hammer C, Bönisch H, Rappold G, Niesler B. (2008) Naturally occurring variants in the HTR3B gene significantly alter properties of human heteromeric 5-hydroxytryptamine-3A/B receptors. Pharmacogenet Genomics. 18(9):793-802

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