Page 16 - T. Protein modification and regulation

[T. Protein modification and regulation-8]

Antipsychotic Drug Clozapine Stabilizes Proteasomal

Substrates by inhibiting the Arg/N-degron Pathway

Jun Hyoung Jeon¹, Min Jae Lee¹˙*

¹Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 03080,

Korea

The N-end rule pathway is one of the ubiquitin-mediated proteolytic mechanism, in which the half-life of a proteins

is determined by the N-terminal residues. RGS4, a member of the small regulator of G protein signaling (RGS) family
and a negative regulator of the G protein signaling pathway, is a bona fide substrate of the arginylation branch of
the N-end rule pathway (Arg/N-end rule pathway) in vivo. RGS4 was also reported to be linked, both genetically

and functionally, with schizophrenia. Here, we report that clozapine, one of the antipsychotic drugs, stabilized RGS4
proteins by inhibiting the Arg/N-end rule pathway. Clozapine significantly increased the level of overexpressed wild-

type RGS4, while had little effects on RGS4(C2V) mutants. In addition, Arg-GFP, a model Arg/N-end rule substrate,
but not Met-GFP control protein, also showed strong stabilization in the presence of clozapine. Transcriptional

expression of RGS4 or cellular activity of proteasomes were not altered by clozapine. Overall, these results provide
possible therapeutic mechanism of the antipsychotics, which mediates the inhibition of RGS4 degradation, also

suggesting a novel molecular etiology of many mental disorders involving the Arg/N-end rule pathway.