The fetal and neonatal brain protein neuronatin protects PC12 cells against certain types of toxic insult.
The protein neuronatin is expressed in the nervous system of the fetus and neonate at a much higher level than in the adult. Its function is unknown. As a result of variable splicing, neuronatin mRNA exists in two forms, alpha and beta. Wild type PC12 cells express neuronatin-alpha. We have isolated a PC12 variant, called 1.9, that retains many of the neuron-like properties of wild type PC12 cells, but it does not express neuronatin and it exhibits markedly increased sensitivity to the toxic effects of nigericin, rotenone and valinomycin. Pretreatment of the 1.9 cells with alpha-methyltyrosine, which inhibits dopamine synthesis, had little effect on the cells' sensitivity to nigericin, rotenone or valinomycin indicating that dopamine-induced oxidative stress was not involved in the toxicity of these compounds. However, flattened cell subvariants of the 1.9 cells, which do not have any neuron-specific characteristics, did not exhibit increased sensitivity to nigericin indicating that some neuronal characteristic of the 1.9 cells contributed to the toxicity of nigericin. After the neuronatin-beta gene was transfected into and expressed in the 1.9 cells, they regained wild type PC12 levels of resistance to nigericin, rotenone and valinomycin. These studies suggest that the function of neuronatin during development could be to protect developing cells from toxic insult occurring during that period.
Zheng
Shuang
S
Department of Biological Chemistry, School of Medicine, University of California, Los Angeles, 650 Charles Young Drive, Los Angeles, CA 90095, USA.
Chou
Alice H
AH
Jimenez
Amie L
AL
Khodadadi
Omid
O
Son
Sarah
S
Melega
William P
WP
Howard
Bruce D
BD
D000818:Animals; D000831:Animals, Newborn / Q000254:growth & development / Q000378:metabolism*; D001921:Brain / Q000196:embryology / Q000254:growth & development / Q000378:metabolism*; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism; D050482:Catecholamine Plasma Membrane Transport Proteins; D016923:Cell Death / Q000187:drug effects / Q000235:genetics*; D002454:Cell Differentiation / Q000502:physiology; D048429:Cell Size / Q000187:drug effects / Q000502:physiology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D004351:Drug Resistance / Q000235:genetics*; D005333:Fetus / Q000196:embryology / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D007476:Ionophores / Q000494:pharmacology; D008543:Melanins / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D009498:Neurotoxins / Q000378:metabolism*; D009550:Nigericin / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D016716:PC12 Cells; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology; D014475:Uncoupling Agents / Q000494:pharmacology; D014634:Valinomycin / Q000494:pharmacology; D019805:alpha-Methyltyrosine / Q000494:pharmacology
D002352:Carrier Proteins; D050482:Catecholamine Plasma Membrane Transport Proteins; D017077:Culture Media, Conditioned; D007476:Ionophores; D008543:Melanins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D017382:Reactive Oxygen Species; C493212:Slc22a1 protein, rat; D014475:Uncoupling Agents; C014121:neuromelanin; D012402:Rotenone; C088089:Nnat protein, rat; D014634:Valinomycin; D019805:alpha-Methyltyrosine; D009550:Nigericin; D004298:Dopamine