Original articles
Jinghui Zhang, Zhou Yu, Guofeng You. Insulin-like growth factor 1 modulates the phosphorylation, expression, and activity of organic anion transporter 3 through protein kinase A signaling pathway[J]. Acta Pharmaceutica Sinica B, 2020, 10(1): 186-194

Insulin-like growth factor 1 modulates the phosphorylation, expression, and activity of organic anion transporter 3 through protein kinase A signaling pathway
Jinghui Zhang, Zhou Yu, Guofeng You
Department of Pharmaceutics, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
Abstract:
Organic anion transporter 3 (OAT3) plays a vital role in removing a broad variety of anionic drugs from kidney, thus avoiding their possible toxicity in the body. In the current study, we investigated the role of insulin-like growth factor 1 (IGF-1) in the regulation of OAT3. We showed that IGF-1 induced a dose- and time-dependent increase in OAT3 transport activity, which correlated well with an increase in OAT3 expression. The IGF-1-induced increase in OAT3 expression was blocked by protein kinase A (PKA) inhibitor H89. Moreover, IGF-1 induced an increase in OAT3 phosphorylation, which was also blocked by H89. These data suggest that the IGF-1 modulation of OAT3 occurred through PKA signaling pathway. To further confirm the involvement of PKA, we treated OAT3-expressing cells with PKA activator Bt2-cAMP, followed by examining OAT activity and phosphorylation. We showed that OAT3 activity and phosphorylation were much enhanced in Bt2-cAMP-treated cells as compared to that in control cells. Finally, linsitinib, an anticancer drug that blocks the IGF-1 receptor, abrogated IGF-1-stimulated OAT3 transport activity. In conclusion, our study demonstrated that IGF-1 regulates OAT3 expression and transport activity through PKA signaling pathway, possibly by phosphorylating the transporter.
Key words:    Organic anion transporter    Drug transport    Regulation    IGF-1    PKA    Phosphorylation   
Received: 2019-02-08     Revised: 2019-04-10
DOI: 10.1016/j.apsb.2019.05.005
Funds: This work was supported by grants (to Dr. Guofeng You) from National Institute of General Medical Sciences (R01-GM079123 and R01-GM097000, USA).
Corresponding author: Guofeng You     Email:gyou@pharmacy.rutgers.edu
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Jinghui Zhang
Zhou Yu
Guofeng You

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