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Deletion of the secretory vesicle proteins IA-2 and IA-2β disrupts circadian rhythms of cardiovascular and physical activity

Soo Mi Kim^*, Andrea Power, Timothy M. Brown, Cara M. Constance^||,1, Steven L. Coon, Takuya Nishimura, Hiroki Hirai, Tao Cai, Christoph Eisner^*, David R. Weaver^¶, Hugh D. Piggins, David C. Klein, Jürgen Schnermann^* and Abner L. Notkins^,2

^* Kidney Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases,

Section on Neuroendocrinology, Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and

Experimental Medicine Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA;

Faculty of Life Sciences, the University of Manchester, Manchester, UK;

^|| Department of Biology, College of the Holy Cross, Worcester, Massachusetts, USA; and

^¶ Department of Neurobiology, University of Massachusetts Medical School, Worcester, Massachusetts, USA

² Correspondence: Experimental Medicine Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Dr., Bethesda, MD 20892, USA. E-mail: anotkins{at}mail.nih.gov

Targeted deletion of IA-2 and IA-2β, major autoantigens in type 1 diabetes and transmembrane secretory vesicle proteins, results in impaired secretion of hormones and neurotransmitters. In the present study, we evaluated the effect of these deletions on daily rhythms in blood pressure, heart rate, core body temperature, and spontaneous physical and neuronal activity. We found that deletion of both IA-2 and IA-2β profoundly disrupts the usual diurnal variation of each of these parameters, whereas the deletion of either IA-2 or IA-2β alone did not produce a major change. In situ hybridization revealed that IA-2 and IA-2β transcripts are highly but nonrhythmically expressed in the suprachiasmatic nuclei, the site of the brain’s master circadian oscillator. Electrophysiological studies on tissue slices from the suprachiasmatic nuclei showed that disruption of both IA-2 and IA-2β results in significant alterations in neuronal firing. From these studies, we concluded that deletion of IA-2 and IA-2β, structural proteins of secretory vesicles and modulators of neuroendocrine secretion, has a profound effect on the circadian system.—Kim, S. M., Power, A., Brown, T. M., Constance, C. M., Coon, S. L., Nishimura, T., Hirai, H., Cai, T., Eisner, C., Weaver, D. R., Piggins, H. D., Klein, D. C., Schnermann, J., Notkins, A. L. Deletion of the secretory vesicle proteins IA-2 and IA-2β disrupts circadian rhythms of cardiovascular and physical activity.

Key Words: blood pressure • heart rate • temperature • diabetes • behavior