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.
Kidney Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
Soo Mi
SM
Kim
Andrea
A
Power
Timothy M
TM
Brown
Cara M
CM
Constance
Steven L
SL
Coon
Takuya
T
Nishimura
Hiroki
H
Hirai
Tao
T
Cai
Christoph
C
Eisner
David R
DR
Weaver
Hugh D
HD
Piggins
David C
DC
Klein
Jürgen
J
Schnermann
Abner L
AL
Notkins
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