Document Detail


Heme reversibly damps PERIOD2 rhythms in mouse suprachiasmatic nucleus explants.
MedLine Citation:
PMID:  19698763     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The hypothalamic suprachiasmatic nucleus (SCN), which in mammals serves as the master circadian pacemaker by synchronizing autonomous clocks in peripheral tissues, is composed of coupled single-cell oscillators that are driven by interlocking positive/negative transcriptional/translational feedback loops. Several studies have suggested that heme, a common prosthetic group that is synthesized and degraded in a circadian manner in the SCN, may modulate the function of several feedback loop components, including the REV-ERB nuclear receptors and PERIOD2 (PER2). We found that ferric heme (hemin, 3-100 microM) dose-dependently and reversibly damped luminescence rhythms in SCN explants from mice expressing a PER2::LUCIFERASE (PER2::LUC) fusion protein. Inhibitors of heme oxygenases (HOs, which degrade heme to biliverdin, carbon monoxide, and iron) mimicked heme's effects on PER2 rhythms. In contrast, heme and HO inhibition did not damp luminescence rhythms in thymus and esophagus explants and had only a small effect on PER2::LUC damping in spleen explants, suggesting that heme's effects are tissue-specific. Analysis of the effects of heme's degradation products on SCN PER2::LUC rhythms indicated that they probably were not responsible for heme's effects on rhythms. The heme synthesis inhibitor N-methylprotoporphyrinIX (NMP) lengthened the circadian period of SCN PER2::LUC rhythms by about an hour. These data are consistent with an important role for heme in the circadian system.
Authors:
C J Guenthner; D Bickar; M E Harrington
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2009-08-19
Journal Detail:
Title:  Neuroscience     Volume:  164     ISSN:  1873-7544     ISO Abbreviation:  Neuroscience     Publication Date:  2009 Dec 
Date Detail:
Created Date:  2009-10-14     Completed Date:  2010-02-12     Revised Date:  2013-05-31    
Medline Journal Info:
Nlm Unique ID:  7605074     Medline TA:  Neuroscience     Country:  United States    
Other Details:
Languages:  eng     Pagination:  832-41     Citation Subset:  IM    
Affiliation:
Department of Psychology and Program in Neuroscience, Smith College, Clark Science Center, 44 College Lane, Northampton, MA 01063, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Central Nervous System Agents / pharmacology
Circadian Rhythm / drug effects,  physiology
Esophagus / physiology
Female
Gene Knock-In Techniques
Heme / metabolism*
Heme Oxygenase (Decyclizing) / antagonists & inhibitors,  metabolism
Hemin / metabolism
Luciferases / genetics,  metabolism
Male
Mice
Mice, Transgenic
Period Circadian Proteins / genetics,  metabolism*
Periodicity*
Protoporphyrins / pharmacology
Spleen / physiology
Suprachiasmatic Nucleus / drug effects,  physiology*
Thymus Gland / physiology
Grant Support
ID/Acronym/Agency:
R21 CA125215-02/CA/NCI NIH HHS; R21CA125215/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Central Nervous System Agents; 0/Per2 protein, mouse; 0/Period Circadian Proteins; 0/Protoporphyrins; 14875-96-8/Heme; 16009-13-5/Hemin; 79236-56-9/N-methylprotoporphyrin IX; EC 1.13.12.-/Luciferases; EC 1.14.99.3/Heme Oxygenase (Decyclizing)
Comments/Corrections

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