Rhythmicity of the cGMP-related signal transduction pathway in the mammalian circadian system.
Entrainment of mammalian circadian rhythms requires the activation of specific signal transduction pathways in the suprachiasmatic nuclei (SCN). Pharmacological inhibition of kinases such as cGMP-dependent kinase (PKG) or Ca2+/calmodulin-dependent kinase, but not cAMP-dependent kinase, blocks the circadian responses to light in vivo. Here we show a diurnal and circadian rhythm of cGMP levels and PKG activity in the hamster SCN, with maximal values during the day or subjective day. This rhythm depends on phosphodiesterase but not on guanylyl cyclase activity. Five-minute light pulses increased cGMP levels at the end of the subjective night [circadian time 18 (CT18)], but not at CT13.5. Western blot analysis indicated that the PKG II isoform is the one present in the SCN. Inhibition of PKG or guanylyl cyclase in vivo significantly attenuated light-induced phase shifts at CT18 (after 5-min light pulses) but did not affect c-Fos expression in the SCN. These results suggest that cGMP and PKG are related to SCN responses to light and undergo diurnal and circadian changes.
Ferreyra
G A
GA
Departamento de Ciencia y Tecnología, Universidad Nacional de Quilmes, 1876 Buenos Aires, Argentina.
Golombek
D A
DA
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism; D000470:Alkaloids / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000502:physiology; D002227:Carbazoles; D002940:Circadian Rhythm / Q000187:drug effects / Q000502:physiology*; D006224:Cricetinae; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006152:Cyclic GMP / Q000502:physiology*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism*; D003624:Darkness; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007211:Indoles; D007276:Injections, Intraventricular; D007527:Isoenzymes / Q000378:metabolism; D008027:Light; D008297:Male; D008322:Mammals; D008647:Mesocricetus; D009043:Motor Activity / Q000502:physiology*; D010069:Oxadiazoles / Q000494:pharmacology; D017440:Photoperiod; D011810:Quinoxalines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013493:Suprachiasmatic Nucleus / Q000187:drug effects / Q000502:physiology*
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D000470:Alkaloids; D002227:Carbazoles; D004791:Enzyme Inhibitors; D007211:Indoles; D007527:Isoenzymes; D010069:Oxadiazoles; D011810:Quinoxalines; C073601:KT 5823; D017868:Cyclic AMP-Dependent Protein Kinases; D017869:Cyclic GMP-Dependent Protein Kinases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D006152:Cyclic GMP; D015056:1-Methyl-3-isobutylxanthine