title: Purine metabolism during neuronal differentiation: the relevance of purine synthesis and recycling.
abstract: 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 (HGprt). 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 PC6-3 cells, a PC12 pheochromocytoma subclone that undergoes robust differentiation with nerve growth factor. The results were compared with five new independent PC6-3 subclones with defective purine recycling because of different mutations affecting HGprt 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 HGprt-mediated purine recycling also is associated with significant loss of dopamine and related metabolites in the mutant PC6-3 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.
authors.affiliation: Department of Neurology, Emory University, Atlanta, Georgia, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Göttle
authors.forename: Heike
authors.initials: H
authors.lastname: Burhenne
authors.forename: Diane
authors.initials: D
authors.lastname: Sutcliffe
authors.forename: H A
authors.initials: HA
authors.lastname: Jinnah
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D004298:Dopamine / Q000378:metabolism; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D009154:Mutation; D020932:Nerve Growth Factor / Q000494:pharmacology; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D050479:Neurotransmitter Transport Proteins / Q000378:metabolism; D016716:PC12 Cells; D011687:Purines / Q000378:metabolism*; D051381:Rats
chemical_list: D050479:Neurotransmitter Transport Proteins; D011687:Purines; D020932:Nerve Growth Factor; D007041:Hypoxanthine Phosphoribosyltransferase; D004298:Dopamine
keywords: Lesch-Nyhan disease; dopamine neurons; hypoxanthine-guanine phosphoribosyltransferase; purine nucleotide