ORL1 receptor-mediated down-regulation of mPER2 in the suprachiasmatic nucleus accelerates re-entrainment of the circadian clock following a shift in the environmental light/dark cycle.
The circadian pacemaker in the suprachiasmatic nucleus (SCN) generates the near 24-h period of the circadian rhythm and is entrained to the 24-h daily cycle by periodic environmental signals, such as the light/dark cycle (photic signal), and can be modulated by various drugs (non-photic signals). The mechanisms by which non-photic signals modulate the circadian clock are not well understood in mice. In mice, many reportedly non-photic stimuli have little effect on the circadian rhythm in vivo. Herein, we investigated the molecular mechanism in W-212393-induced phase advance using mice. W-212393 caused a significant phase advance of locomotor activity rhythm in mice at subjective day. Injection of W-212393 during subjective day elicited down-regulation of mPER2 protein in the SCN shell region, but not mPer2 mRNA. Administration of W-212393 during subjective day failed to produce phase advance in mPer2-mutant mice as well as in ORL1 receptor deficient mice. Furthermore, we show that such inhibition of mPER2 accelerates re-entrainment of the circadian clock following an abrupt shift in the environmental light/dark cycle, such as occurs with transmeridian flight. The present results suggest that post-translational down-regulation of mPER2 protein in the shell region of mouse SCN may be involved in W-212393-induced non-photic phase advance.
Miyakawa
Kazuko
K
Department of Electrical Engineering and Bioscience, School of Science and Engineering, Waseda University, 2-7-5 Higashifushimi, Nishitokyo, Tokyo 202-0021, Japan.
Uchida
Ayumi
A
Shiraki
Tomomi
T
Teshima
Koji
K
Takeshima
Hiroshi
H
Shibata
Shigenobu
S
D000073:Acenaphthenes / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal; D001562:Benzimidazoles / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002940:Circadian Rhythm; D004307:Dose-Response Relationship, Radiation; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D004777:Environment; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology / Q000528:radiation effects; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D056950:Period Circadian Proteins; D010775:Photic Stimulation; D012333:RNA, Messenger / Q000096:biosynthesis; D011957:Receptors, Opioid / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013493:Suprachiasmatic Nucleus / Q000378:metabolism*; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000094942:Nociceptin Receptor
C505961:2-(3-(1-(acenaphthen-1-yl)piperidin-4-yl)-2,3-dihydro-2-oxobenzimidazol-1-yl)-N-methylacetamide; D000073:Acenaphthenes; D001562:Benzimidazoles; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D012333:RNA, Messenger; D011957:Receptors, Opioid; D014157:Transcription Factors; D000094942:Nociceptin Receptor; C000722287:Oprl1 protein, mouse