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Purine metabolism during neuronal differentiation: the relevance of purine synthesis and recycling
Author(s) -
Göttle Martin,
Burhenne Heike,
Sutcliffe Diane,
Jinnah H. A.
Publication year - 2013
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12366
Subject(s) - purine metabolism , purine , hypoxanthine guanine phosphoribosyltransferase , biology , dopaminergic , biochemistry , hypoxanthine , phosphoribosyltransferase , dopamine , microbiology and biotechnology , enzyme , endocrinology , mutant , gene
Purines are a class of small organic molecules that are essential for all cells. They play critical roles in neuronal differentiation and function. Their importance is highlighted by several inherited disorders of purine metabolism, such as Lesch–Nyhan disease, which is caused by a deficiency of the purine salvage enzyme, hypoxanthine‐guanine phosphoribosyltransferase ( HG prt). Despite the known importance of purines in the nervous system, knowledge regarding their metabolism in neurons is limited. In the current studies, purine pools and their metabolism were examined in rat PC 6‐3 cells, a PC 12 pheochromocytoma subclone that undergoes robust differentiation with nerve growth factor. The results were compared with five new independent PC 6‐3 subclones with defective purine recycling because of different mutations affecting HG prt enzyme activity. The results demonstrate an increase in most purines and in energy state following neuronal differentiation, as well as specific abnormalities when purine recycling is lost. The loss of HG prt‐mediated purine recycling also is associated with significant loss of dopamine and related metabolites in the mutant PC 6‐3 lines, suggesting an important connection between purine and dopamine pathways. These results provide insights into how purine pools and metabolism change with neuronal differentiation, and how specific enzyme defects may cause neuronal dysfunction.Differentiation of dopaminergic PC6‐3 cells is accompanied by increased purine pools and energy state. The lack of a functional purine recycling pathway causes purine limitation in both undifferentiated and differentiated cells, as well as profound loss of dopamine content. The results imply an unknown mechanism by which intracellular purine levels regulate dopamine levels.