title: Glutamate regulates the activity of topoisomerase I in mouse cerebellum.
abstract: Topoisomerase I (topo I) is a nuclear enzyme which participates in most DNA transactions. It was shown to be inhibited in depolarized neurons by poly adenosine diphosphate (ADP)-ribosylation of the enzyme protein. We demonstrated previously an age and sex dependent topo I activity and enzyme protein level in the various regions of mouse brain. A specific distribution pattern of topo I was observed and the inhibitory neurons exhibited the highest enzyme activity and protein level in both the nucleus and the cytoplasm. Here, we show that neurotransmitters (glutamate and gamma-aminobutyric acid (GABA)) regulate the activity of topo I in mouse cerebellum sections. Glutamate exhibited a significant time-dependent inhibition of topo I activity but no effect of the enzyme protein level. GABA in contrary only slightly and transiently inhibited topo I activity. The inhibitory effect of glutamate was mediated by Ca(+2) and by ADP-ribosylation of topo I protein and the glutamate ionotropic receptors were involved. Glutamate also diminished the inhibitory effect of topotecan on topo I. These results point to distinct and highly specific effects of the major neurotransmitters on topo I activity in the cerebellum suggesting that topo I possesses a specific role in the brain which differs from its known biological functions.
authors.affiliation: The Shraga Segal Department of Microbiology & Immunology, Ben-Gurion University Cancer Research Center, Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, 84105, Israel.
authors.forename: Eldar
authors.initials: E
authors.lastname: Zehorai
authors.forename: Erez
authors.initials: E
authors.lastname: Eitan
authors.forename: Michal
authors.initials: M
authors.lastname: Hershfinkel
authors.forename: Israel
authors.initials: I
authors.lastname: Sekler
authors.forename: Esther
authors.initials: E
authors.lastname: Priel
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000494:pharmacology; D002467:Cell Nucleus / Q000201:enzymology; D002531:Cerebellum / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D003593:Cytoplasm / Q000201:enzymology; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004587:Electrophoresis, Agar Gel; D005455:Fluorescent Antibody Technique; D018698:Glutamic Acid / Q000378:metabolism* / Q000494:pharmacology; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D051379:Mice; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D059004:Topoisomerase I Inhibitors; D019772:Topotecan / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D059004:Topoisomerase I Inhibitors; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D019772:Topotecan; D011065:Poly(ADP-ribose) Polymerases; D004264:DNA Topoisomerases, Type I; D002118:Calcium