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Multiple treatments with L‐3,4‐dihydroxyphenylalanine modulate dopamine biosynthesis and neurotoxicity through the protein kinase A‐transient extracellular signal‐regulated kinase and exchange protein activation by cyclic AMP‐sustained extracellular signal‐regulated kinase signaling pathways
Author(s) -
Park Keun Hong,
Park Hyun Jin,
Shin Keon Sung,
Lee Myung Koo
Publication year - 2014
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.23450
Subject(s) - protein kinase a , phosphorylation , microbiology and biotechnology , dopamine , extracellular , tyrosine hydroxylase , kinase , creb , intracellular , biology , endocrinology , medicine , chemistry , biochemistry , gene , transcription factor
Multiple treatments with L‐3,4‐dihydroxyphenylalanine (L‐DOPA; 20 µM) induce neurite‐like outgrowth and reduce dopamine biosynthesis in rat adrenal pheochromocytoma (PC) 12 cells. We therefore investigated the effects of multiple treatments with L‐DOPA (MT‐LD) on cell survival and death over a duration of 6 days by using PC12 cells and embryonic rat midbrain primary cell cultures. MT‐LD (10 and 20 µM) decreased cell viability, and both types of cells advanced to the differentiation process at 4–6 days. MT‐LD induced cyclic adenosine monophosphate (cAMP)‐dependent protein kinase A (PKA) phosphorylation and exchange protein activation by cAMP (Epac) expression at 1–3 days, which led to transient extracellular signal‐regulated kinase (ERK1/2) phosphorylation in both cells. In these states, MT‐LD activated cAMP‐response element binding protein (CREB; Ser133) and tyrosine hydroxylase (Ser40) phosphorylation in PC12 cells, which led to an increase in intracellular dopamine levels. In contrast, MT‐LD induced prolonged Epac expression at 4–5 days in both cells, which led to sustained ERK1/2 phosphorylation. In these states, the dopamine levels were decreased in PC12 cells. In addition, MT‐LD induced c‐Jun N‐terminal kinase1/2 phosphorylation and cleaved caspase‐3 expression at 4–6 days in both cells. These results suggest that MT‐LD maintains cell survival via PKA‐transient ERK1/2 activation, which stimulates dopamine biosynthesis. In contrast, at the later time period, MT‐LD induces differentiation via both prolonged Epac and sustained ERK1/2 activation, which subsequently leads to the cell death process. Our data demonstrate that L‐DOPA can cause neurotoxicity by modulating the Epac‐ERK pathways in neuronal and PC12 cells. © 2014 Wiley Periodicals, Inc.