Cholecystokinin-A receptors regulate photic input pathways to the circadian clock Takao Shimazoe * , Mitsutaka Morita * , Shinichiro Ogiwara † , Tomoyoshi Kojiya † , Junpei Goto † , Masaki Kamakura ‡ , Takahiro Moriya § , Kazuyuki Shinohara § , Soichi Takiguchi || , Akira Kono || , Kyoko Miyasaka ¶ , Akihiro Funakoshi || and Masayuki Ikeda † ,# ,1 * Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan; † Graduate School of Science and Engineering, University of Toyama, Toyama, Japan; ‡ Biotechnology Research Center, Faculty of Engineering, Toyama Prefectural University, Toyama, Japan; § Department of Translational Medical Sciences, Course of Medical and Dental Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; || National Kyushu Cancer Center, Fukuoka, Japan; ¶ Department of Translational Medical Sciences, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan; and # Advanced Institute for Biological Science, Waseda University, Tokyo, Japan 1 Correspondence: Department of Biology, Faculty of Science, University of Toyama, Rm. B214, 3190 Gofuku, Toyama-city, Toyama 930-8555, Japan. E-mail: msikeda@sci.u-toyama.ac.jp 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, T., Morita, M., Ogiwara, S., Kojiya, T., Goto, J., Kamakura, M., Moriya, T., Shinohara, K., Takiguchi, S., Kono, A., Miyasaka, K., Funakoshi, A., Ikeda, M. Cholecystokinin-A receptors regulate photic input pathways to the circadian clock. Key Words: cholecystokinin-A receptor mutant mice • glycinergic amacrine cells • melanopsin retinal ganglion cells • suprachiasmatic nucleus neurons

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