The molecular gatekeeper Dexras1 sculpts the photic responsiveness of the mammalian circadian clock.
The mammalian master clock, located in the suprachiasmatic nucleus (SCN), is exquisitely sensitive to photic timing cues, but the key molecular events that sculpt both the phasing and magnitude of responsiveness are not understood. Here, we show that the Ras-like G-protein Dexras1 is a critical factor in these processes. Dexras1-deficient mice (dexras1-/-) exhibit a restructured nighttime phase response curve and a loss of gating to photic resetting during the day. Dexras1 affects the photic sensitivity by repressing or activating time-of-day-specific signaling pathways that regulate extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK). During the late night, Dexras1 limits the capacity of pituitary adenylate cyclase (PAC) activating peptide (PACAP)/PAC1 to affect ERK/MAPK, and in the early night, light-induced phase delays, which are mediated predominantly by NMDA receptors, are reduced as reported previously. Daytime photic phase advances are mediated by a novel signaling pathway that does not affect the SCN core but rather stimulates ERK/MAPK in the SCN shell and triggers downregulation of clock protein expression.
Cheng
Hai-Ying M
HY
Department of Neuroscience, The Ohio State University, Columbus, Ohio 43210, USA. hymcheng@yahoo.ca
Dziema
Heather
H
Papp
Joseph
J
Mathur
Daniel P
DP
Koletar
Margaret
M
Ralph
Martin R
MR
Penninger
Josef M
JM
Obrietan
Karl
K
D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001683:Biological Clocks / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D010775:Photic Stimulation / Q000379:methods*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013493:Suprachiasmatic Nucleus / Q000201:enzymology / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000502:physiology*
D048049:Extracellular Signal-Regulated MAP Kinases; C498511:Rasd1 protein, mouse; D018631:ras Proteins