The circadian organization of behavior plays a critical role in an organisms's response to social and light/dark cycles encountered on a daily and seasonal basis. Alterations in the normal function of the mammalian biological clock, located in the suprachiasmatic nucleus (SCN), leads to a variety of neurological abnormalities including sleep disorders, depression, and mental fatigue. A feedback regulator of circadian rhythmicity is the neurohormone melatonin. Changes in environmental light information received by the SCN are converted into the nocturnal synthesis and release of melatonin from the pineal gland. An important regulatory of melatonin synthesis and circadian clock function is cAMP. cAMP regulates the transcription of several proteins critical for the circadian expression of melatonin, including serotonin N-acetyltransferase (NAT), which is responsible for catalyzing the synthesis of melatonin from serotonin. Additionally, cAMP may also play an important role in circadian timekeeping in the SCN by regulating gene transcription. By integrating different intracellular signal transduction pathways, the Ca2+/calmodulin-sensitive adenylyl cyclases may play an important role regulating circadian rhythmicity. With the two unique tools developed in the laboratory of Dr. Storm (mutant mice lacking Ca2+/calmodulin-sensitive adenylyl cyclases and a CRE-lacZ transgenic mouse strain), I propose to elucidate the roles Ca2+/calmodulin-sensitive adenylyl cyclases play in melatonin synthesis and in the modulation of SCN circadian rhythmicity and to determine whether CRE-mediated transcription in the SCN and pineal gland is regulated in a circadian manner.
| 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 |
