Document Detail

Decreased GTP-stimulated adenylyl cyclase activity in HPRT-deficient human and mouse fibroblast and rat B103 neuroblastoma cell membranes.
MedLine Citation:
PMID:  16336632     Owner:  NLM     Status:  MEDLINE    
Defect of the purine salvage enzyme, hypoxanthine phosphoribosyl transferase (HPRT), results in Lesch-Nyhan disease (LND). It is unknown how the metabolic defect translates into the severe neuropsychiatric phenotype characterized by self-injurious behavior, dystonia and mental retardation. There are abnormalities in GTP, UTP and CTP concentrations in HPRT-deficient cells. Moreover, GTP, ITP, XTP, UTP and CTP differentially support Gs-protein-mediated adenylyl cyclase (AC) activation. Based on these findings we hypothesized that abnormal AC regulation may constitute the missing link between HPRT deficiency and the neuropsychiatric symptoms in LND. To test this hypothesis, we studied AC activity in membranes from primary human skin and immortalized mouse skin fibroblasts, mouse Neuro-2a neuroblastoma cells and rat B103 neuroblastoma cells. In B103 control membranes, GTP, ITP, XTP and UTP exhibited profound stimulatory effects on basal AC activity that approached the effects of hydrolysis-resistant nucleotide analogs. In HPRT- membranes, the stimulatory effects of GTP, ITP, XTP and UTP were strongly reduced. Similarly, in human and mouse skin fibroblast membranes we also observed a decrease in GTP-stimulated AC activity in HPRT-deficient cells compared with the respective controls. In mouse Neuro-2a neuroblastoma membranes, AC activity in the presence of GTP was below the detection limit of the assay. We discuss several possibilities to explain the abnormalities in AC regulation in HPRT deficiency that encompass various species and cell types.
Cibele S Pinto; Roland Seifert
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2005-12-08
Journal Detail:
Title:  Journal of neurochemistry     Volume:  96     ISSN:  0022-3042     ISO Abbreviation:  J. Neurochem.     Publication Date:  2006 Jan 
Date Detail:
Created Date:  2005-12-22     Completed Date:  2006-02-17     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  2985190R     Medline TA:  J Neurochem     Country:  England    
Other Details:
Languages:  eng     Pagination:  454-9     Citation Subset:  IM    
Department of Pharmacology and Toxicology, University of Kansas, Lawrence, USA.
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MeSH Terms
Adenylate Cyclase / metabolism*
Cell Line
Cell Membrane / enzymology*
Fibroblasts / enzymology*
Guanosine Triphosphate / pharmacology,  physiology*
Hypoxanthine Phosphoribosyltransferase / deficiency*
Lesch-Nyhan Syndrome / enzymology,  psychology
Mice, Knockout
Neuroblastoma / enzymology*,  pathology
Reg. No./Substance:
86-01-1/Guanosine Triphosphate; EC Phosphoribosyltransferase; EC Cyclase

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