The circadian organization of behavior determines how complex organisms respond to light/dark cues on a daily and seasonal basis. Disruption of the circadian rhythm in humans can lead to sleep disorders, mental fatigue, and depression, particularly with aging patients. The daily cycle of melatonin synthesis in the pineal is controlled by the circadian clock in the suprachiasmatic nucleus (SCN). Melatonin may stabilize the sleep cycle by maintaining steady-state entrainment of circadian pacemakers. Melatonin biosynthesis in the pineal and retina is regulated by cAMP which stimulates transcription of genes encoding enzymes important for circadian expression of melatonin. Nocturnal release of norepinephrine at the pineal increases cAMP by activation of beta- and alpha-1-adrenergic receptors. Calcium stimulated adenylyl cyclases (AC1 and AC8) may play a major role in regulating melatonin biosynthesis because of their unique regulatory properties. The applicants hypothesize that costimulation of AC1 by Ca++ and beta-adrenergic receptors may generate cAMP signals of sufficient strength and duration to regulate the transcription of specific genes important for melatonin synthesis. They hypothesize that the diurnal variation in expression of AC1 and its stimulation by nocturnal NE regulates the synthesis of melatonin. Furthermore, they hypothesize that cAMP may also play an important role in circadian time keeping in the SCN by regulating gene transcription through the cAMP response element (CRE). The overall goals of this project are to define the role of the Ca++-stimulated adenylyl cyclases and CRE-mediated transcription in the regulation of melatonin synthesis and in circadian rhythm. This proposal uses two unique tools developed in this laboratory; mutant mice lacking Ca++-sensitive adenylyl cyclases and a CRE-lacZ transgenic mouse strain that is used to monitor CRE-mediated transcription in vivo.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurological Sciences Subcommittee 1 (NLS)
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Nichols, Paul L
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University of Washington
Schools of Medicine
United States
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DiRocco, Derek P; Scheiner, Zachary S; Sindreu, Carlos Balet et al. (2009) A role for calmodulin-stimulated adenylyl cyclases in cocaine sensitization. J Neurosci 29:2393-403
Nicol, Xavier; Bennis, Mohammed; Ishikawa, Yoshihiro et al. (2006) Role of the calcium modulated cyclases in the development of the retinal projections. Eur J Neurosci 24:3401-14
Chan, Guy C-K; Tonegawa, Susumu; Storm, Daniel R (2005) Hippocampal neurons express a calcineurin-activated adenylyl cyclase. J Neurosci 25:9913-8
Chen, Xi; Garelick, Michael G; Wang, Hongbing et al. (2005) PI3 kinase signaling is required for retrieval and extinction of contextual memory. Nat Neurosci 8:925-31
Fukuhara, Chiaki; Liu, Cuimei; Ivanova, Tamara N et al. (2004) Gating of the cAMP signaling cascade and melatonin synthesis by the circadian clock in mammalian retina. J Neurosci 24:1803-11
Yang, Huaitao; Scholich, Klaus; Poser, Steve et al. (2002) Developmental expression of PAM (protein associated with MYC) in the rodent brain. Brain Res Dev Brain Res 136:35-42
Chan, G C; Lernmark, U; Xia, Z et al. (2001) DNA elements of the type 1 adenylyl cyclase gene locus enhance reporter gene expression in neurons and pinealocytes. Eur J Neurosci 13:2054-66
Wong, S T; Athos, J; Figueroa, X A et al. (1999) Calcium-stimulated adenylyl cyclase activity is critical for hippocampus-dependent long-term memory and late phase LTP. Neuron 23:787-98
Obrietan, K; Impey, S; Smith, D et al. (1999) Circadian regulation of cAMP response element-mediated gene expression in the suprachiasmatic nuclei. J Biol Chem 274:17748-56