Sorting nexin 3, a protein upregulated by lithium, contains a novel phosphatidylinositol-binding sequence and mediates neurite outgrowth in N1E-115 cells.
Lithium, a drug in the treatment of bipolar disorder, modulates many aspects of neuronal developmental processes such as neurogenesis, survival, and neuritogenesis. However, the underlying mechanism still remains to be understood. Here, we show that lithium upregulates the expression of sorting nexin 3 (SNX3), one of the Phox (PX) domain-containing proteins involved in endosomal sorting, and regulates neurite outgrowth in mouse N1E-115 neuroblastoma cells. The inhibition of SNX3 function by its knockdown decreases lithium-induced outgrowth of neurites. Transfection of the full-length SNX3 construct into cells facilitates the outgrowth. We also find that the C-terminus, as well as the PX domain, of SNX3 has a functional binding sequence with phosphatidylinositol monophosphates. Transfection of the C-terminal deletion mutant or only the C-terminus does not have an effect on the outgrowth. These results suggest that SNX3, a protein upregulated by lithium, is an as yet unknown regulator of neurite formation and that it contains another functional phosphatidylinositol phosphate-binding region at the C-terminus.
Mizutani
Reiko
R
Department of Pharmacology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya, Tokyo 157-8535, Japan.
Yamauchi
Junji
J
Kusakawa
Shinji
S
Nakamura
Kazuaki
K
Sanbe
Atsushi
A
Torii
Tomohiro
T
Miyamoto
Yuki
Y
Tanoue
Akito
A
D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D018021:Lithium Chloride / Q000494:pharmacology*; D051379:Mice; D008969:Molecular Sequence Data; D016501:Neurites / Q000378:metabolism / Q000502:physiology*; D009447:Neuroblastoma; D010716:Phosphatidylinositols / Q000378:metabolism*; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D058305:Sorting Nexins; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D033921:Vesicular Transport Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
D002352:Carrier Proteins; D010716:Phosphatidylinositols; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; C533230:Snx3 protein, mouse; D058305:Sorting Nexins; D033921:Vesicular Transport Proteins; D018021:Lithium Chloride