A b-arrestin 2 signaling complex mediates lithium action on behavior (Cell, 2008, 132:125-136)

報告日期: 2008/05/27
報告時間: 17:10/18:00
報告學生: 蔡政潔
講評老師: 林以行
附件下載:

http://basicmed.med.ncku.edu.tw/admin/up_img/970527-3.pdf

A b-arrestin 2 Signaling Complex Mediates Lithium Action on Behavior

Beaulieu, J. M. et al. Cell 132: 125-136 (2008).

 

Student: Cheng-Chieh Tsai (蔡政潔)

Commentator: Dr. Yee-Shin Lin (林以行 教授)

T ime: 17:10-18:00, May 27, 2008

Place: Room 602

 

Abstract

Mood stabilizer lithium therapy has used for bipolar disorder, unipolar depression, and schizophrenia; however, the mechanisms remain unclear. Glycogen synthase kinase-3 (GSK-3b) is a ubiquitous and constitutively active serine/threonine kinase. Lithium inhibits GSK-3b activity through a direct manner by competing magnesium. Additionally, lithium also causes an indirect inhibitory effect on GSK-3b by activating several kinases, upstream of GSK-3b, and downregulating several protein phatases, positively regulated on GSK-3b.1 Nevertheless, the molecular mechanism are still unresolved. The authors previously found that lithium antagonized dopamine-dependent behaviors mediated by an Akt/GSK-3b signaling cascade.2 Moreover, Akt, scaffolding protein b-arrestin 2, and protein phosphatase 2A (PP2A) signaling complex mediates dopamine receptor activation and is essential for neurotransmission and behavior.3 In this study, the authors investigated the regulatory mechanism of lithium on Akt/b-arrestin 2/PP2A signaling complex and its effects on behavior. They found that b-arrestin 2 was necessary for the modulation of Akt/GSK-3b phosphorylation by acute and chronic lithium treatment. Besides, lithium targeted GSK-3b and b-arrestin 2 are essential for mediating locomotor activity and anti-depressant-like behavioral. Further results showed that lithium disrupted the pre-assembled Akt/b-arrestin 2/PP2A signaling complex without affecting the integrity of PP2A complex in vitro and in vivo. They also demonstrated that lithium caused destabilization of Akt/b-arrestin 2/PP2A signaling complex through a competition with magnesium. Taken together, these results indicate that the Akt/b-arrestin 2/PP2A signaling complex is involved in the regulation of Akt/GSK-3b signaling and behaviors by lithium treatment.

 

References

1.         Jope, R. S. et al. Lithium and GSK-3: one inhibitor, two inhibitory actions, multiple outcomes. Trends Pharmacol. Sci. 24: 441-443 (2003).

2.         Beaulieu, J. M. et al. Lithium antagonizes dopamine-dependent behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade. Proc. Natl. Acad. Sci. USA 101: 5099-5104 (2004).

3.         Beaulieu, J. M. et al. An Akt/b-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior. Cell 122: 261-273 (2005).