Neurochemical Research

, Volume 32, Issue 8, pp 1292–1301 | Cite as

Effects of Phenylalanine and its Metabolites on Cytoplasmic Free Calcium in Cortical Neurons

  • Y. G. Yu
  • F. G. Tang
  • J. Pan
  • X. F. Gu
Original Paper


Classic phenylketonuria (PKU) is characterized by brain lesions. However, its underlying neurotoxic mechanisms remain unknown. Based on our previous studies, we hypothesized that calcium might participate in PKU-associated neuropathy. In cultured cortical neurons, cytoplasmic free calcium concentration ([Ca2+]i) decreased dramatically when treatment with phenylalanine (Phe) and phenyllactic acid, while phenylacetic acid treatment immediately increased [Ca2+]i, which began to decrease after 3 min. Moreover, [Ca2+]i decreased dramatically after Phe treatment in the presence of EGTA suggesting that Phe might increase [Ca2+]i efflux. Phe-induced [Ca2+]i decrease was strongly inhibited by vanadate, a non-specific plasma membrane Ca2+-ATPase (PMCA) antagonist, suggesting that Phe might increase [Ca2+]i efflux throught modulating PMCA. These findings were further supported by the facts that Phe could increase membrance 45Ca-uptake capability and PMCA activity. In contrast, treatment of KBR7943 or thapsigargin, antagonists to Na/Ca Exchanger (NCX) and Sarco/Endoplasmic reticulum Ca2+-ATPase (SERCA), respectively, did not elicit any changes in [Ca2+]i. Specific siRNA against PMCA had an effect similar to vanadate. Since the brain injury induced by phenylalaninemia was thought to be a chronic process, we cultured cortical neurons in the presence of Phe for 2 weeks and measured [Ca2+]i, PMCA activity and 45Ca-uptake capability at days 3, 7, 9 and 14, respectively. PMCA activity and 45Ca-uptake capability decreased from day 9, at the same time [Ca2+]i increase was observed. In conclusion, PMCA participate in regulating Phe-induced initial rapid decrease in [Ca2+]i and subsequent long-term increase in [Ca2+]i.


Phenylalanine(Phe) Plasma membrane Ca2+-ATPase (PMCA) Calcium Cortical neurons 



This work was supported by grant from the National Natural Science Foundation of China (No. 30471834).


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Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.Department of Endocrinology and Genetic Metabolism, Xinhua HospitalShanghai Jiaotong University School of Medicine, Shanghai Institute for Pediatric ResearchShanghaiChina

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