Pacemaker Neurons and Secreted Factors

Abstract

Three papers this week provide new insights into the molecular mechanisms underlying the establishment and maintenance of circadian rhythms. Cyclic periods of activity and inactivity occur in the absence of changes in light, indicative of an autonomous clock. This cycle also is influenced by light. Nitabach et al. created transgenic flies in which electrical activity in the pacemaker neurons, which control circadian changes in locomotor activity, was suppressed by targeted expression of K + channels. These flies did not exhibit circadian changes in activity in continued dark, nor did the pacemaker cells exhibit molecular oscillation of the Period and Timeless proteins in the dark. Light entrainment of the molecular clock was unaffected, suggesting that the electrical activity of the pacemaker neurons is only essential for molecular periodicity of these neurons in the absence of environmental clues. Two groups investigated the circadian clock in mice. Harmar et al. investigated the circadian clock of mice lacking the receptor VPAC 2 , which recognizes both vasointestinal peptide (VIP) and pituitary adenylate cyclase activating-polypeptide (PACAP) and which is abundant in the suprachiasmatic nuclei (SCN), the site of the mammalian master clock. The VPAC 2 -/- mice exhibited decreased circadian behavior patterns and more rapid reentrainment in response to changes in the light:dark cycle compared with wild-type animals. Furthermore, the rhythmic changes in the clock genes in the SCN were suppressed in the VPAC 2 -/- mice under conditions with a light and dark cycle, and rhythmicity was completely lost in the VPAC 2 -/- SCN in mice kept in constant dark. Cheng et al. provide evidence for prokineticin 2 as a secreted factor that may be a key output of the SCN clock activity in mammals. Prokineticin 2 is expressed in the SCN, the receptor for prokineticin 2 in regions of the brain that are targets of the SCN. The expression of prokineticin 2 is rhythmic and regulated in response to light. Finally, injection of prokineticin 2 into the brains of mice inhibited locomotor activity during the dark phase and increased activity during the light phase. M. N. Nitabach, J. Blau, T. C. Holmes, Electrical silencing of Drosophila pacemaker neurons stops the free-running cicradian clock. Cell 109 , 485-495 (2002). [Online Journal] A. J. Harmar, H. M. Marston, S. Shen, C. Spratt, K. M. West, W. J. Sheward, C. F. Morrison, J. R. Dorin, H. D. Piggins, J.-C. Reubi, J. S. Kelly, E. S. Maywood, M. H. Hastings, The VPAC 2 receptor is essential for cicadian function in the mouse suprachiasmatic nuclei. Cell 109 , 497-508 (2002). [Online Journal] M. Y. Cheng, C. M. Bullock, C. Li, A. G. Lee, J. C. Bermak, J. Belluzzi, D. R. Weaver, F. M. Leslie, Q.-Y. Zhou, Prokineticin 2 transmits the behavioural circadian rhythm of the suprachiasmatic nucleus. Nature 417 , 405-410 (2002). [Online Journal]