Cholecystokinin-A receptors regulate photic input pathways to the circadian clock.
Daily behaviors are strongly dominated by internally generated circadian rhythms, but the underlying mechanisms remain unclear. In mammals, photoentrainment of behaviors to light-dark cycles involves signaling from both intrinsically photosensitive retinal ganglion cells and classic photoreceptor pathways to the suprachiasmatic nucleus (SCN). How classic photoreceptor pathways work with the photosensitive ganglion cells, however, is not fully understood. Although cholecystokinin (CCK) peptide has been shown to be present in a variety of vertebrate retinas, its function at a systems level is also unknown. In the present study we examined a possible role of CCK-A receptors in photoentrainment using CCK-A receptor knockout mice. The lacZ reporter gene within a gene-knockout cassette revealed precise localization of CCK-A receptors in the circadian clock system. We demonstrated that CCK-A receptors were located predominately on glycinergic amacrine cells but were rarely found on SCN neurons. Moreover, Ca(2+) imaging analysis demonstrated that the CCK-A agonist, CCK-8 sulfate (CCK-8s), mobilized intracellular Ca(2+) in amacrine cells but not glutamate-receptive SCN neurons. Furthermore, light pulse-induced mPer1/mPer2 gene expression in SCN, behavioral phase shifts, and the pupillary reflex were significantly reduced in CCK-A receptor knockout mice. These data indicate a novel function of CCK-A receptors in the nonimage-forming photoreception presumably via amacrine cell-mediated signal transduction pathways.
Shimazoe
Takao
T
Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Morita
Mitsutaka
M
Ogiwara
Shinichiro
S
Kojiya
Tomoyoshi
T
Goto
Junpei
J
Kamakura
Masaki
M
Moriya
Takahiro
T
Shinohara
Kazuyuki
K
Takiguchi
Soichi
S
Kono
Akira
A
Miyasaka
Kyoko
K
Funakoshi
Akihiro
A
Ikeda
Masayuki
M
D025042:Amacrine Cells / Q000502:physiology*; D000818:Animals; D002940:Circadian Rhythm / Q000502:physiology*; D008027:Light; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008959:Models, Neurological; D009043:Motor Activity / Q000528:radiation effects; D043886:Receptor, Cholecystokinin A / Q000172:deficiency / Q000502:physiology*; D012025:Reflex, Pupillary / Q000502:physiology; D012844:Sincalide / Q000031:analogs & derivatives / Q000494:pharmacology; D013493:Suprachiasmatic Nucleus / Q000166:cytology / Q000502:physiology / Q000528:radiation effects
C090019:8-sulfocholecystokinin octapeptide; D043886:Receptor, Cholecystokinin A; D012844:Sincalide