Deletion of the secretory vesicle proteins IA-2 and IA-2beta disrupts circadian rhythms of cardiovascular and physical activity.
Targeted deletion of IA-2 and IA-2beta, 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-2beta profoundly disrupts the usual diurnal variation of each of these parameters, whereas the deletion of either IA-2 or IA-2beta alone did not produce a major change. In situ hybridization revealed that IA-2 and IA-2beta 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-2beta results in significant alterations in neuronal firing. From these studies, we concluded that deletion of IA-2 and IA-2beta, structural proteins of secretory vesicles and modulators of neuroendocrine secretion, has a profound effect on the circadian system.
Kim
Soo Mi
SM
Kidney Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
Power
Andrea
A
Brown
Timothy M
TM
Constance
Cara M
CM
Coon
Steven L
SL
Nishimura
Takuya
T
Hirai
Hiroki
H
Cai
Tao
T
Eisner
Christoph
C
Weaver
David R
DR
Piggins
Hugh D
HD
Klein
David C
DC
Schnermann
Jürgen
J
Notkins
Abner L
AL
D000818:Animals; D002940:Circadian Rhythm; D004594:Electrophysiology; D006439:Hemodynamics / Q000502:physiology*; D051379:Mice; D012333:RNA, Messenger / Q000032:analysis; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D022142:Secretory Vesicles / Q000737:chemistry*; D013493:Suprachiasmatic Nucleus / Q000502:physiology
D012333:RNA, Messenger; C516863:Ptprn protein, mouse; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8