title: Tissue-type plasminogen activator-plasmin-BDNF modulate glutamate-induced phase-shifts of the mouse suprachiasmatic circadian clock in vitro.
abstract: The mammalian circadian clock in the suprachiasmatic nucleus (SCN) maintains environmental synchrony through light signals transmitted by glutamate released from retinal ganglion terminals. Brain-derived neurotrophic factor (BDNF) is required for light/glutamate to reset the clock. In the hippocampus, BDNF is activated by the extracellular protease, plasmin, which is produced from plasminogen by tissue-type plasminogen activator (tPA). We provide data showing expression of proteins from the plasminogen activation cascade in the SCN and their involvement in circadian clock phase-resetting. Early night glutamate application to SCN-containing brain slices resets the circadian clock. Plasminogen activator inhibitor-1 (PAI-1) blocked these shifts in slices from wild-type mice but not mice lacking its stabilizing protein, vitronectin (VN). Plasmin, but not plasminogen, prevented inhibition by PAI-1. Both plasmin and active BDNF reversed alpha(2)-antiplasmin inhibition of glutamate-induced shifts. alpha(2)-Antiplasmin decreased the conversion of inactive to active BDNF in the SCN. Finally, both tPA and BDNF allowed daytime glutamate-induced phase-resetting. Together, these data are the first to demonstrate expression of these proteases in the SCN, their involvement in modulating photic phase-shifts, and their activation of BDNF in the SCN, a potential 'gating' mechanism for photic phase-resetting. These data also demonstrate a functional interaction between PAI-1 and VN in adult brain. Given the usual association of these proteins with the extracellular matrix, these data suggest new lines of investigation into the locations and processes modulating mammalian circadian clock phase-resetting.
authors.affiliation: Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee at Knoxville, Knoxville, TN 37996, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Mou
authors.forename: Cynthia B
authors.initials: CB
authors.lastname: Peterson
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Prosser
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism* / Q000494:pharmacology; D002940:Circadian Rhythm / Q000187:drug effects* / Q000502:physiology; D004347:Drug Interactions; D005341:Fibrinolysin / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D018698:Glutamic Acid / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D013493:Suprachiasmatic Nucleus / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D010959:Tissue Plasminogen Activator / Q000378:metabolism* / Q000494:pharmacology; D019096:Vitronectin / Q000172:deficiency
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D017395:Plasminogen Activator Inhibitor 1; D019096:Vitronectin; D018698:Glutamic Acid; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin