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

Kim, Soo Mi; Power, Andrea; Brown, T. M.; Constance, Cara M.; Coon, Steven L.; Nishimura, Takuya; Hirai, Hiroki; Cai, Tao; Eisner, Christoph; Weaver, David R.; Piggins, Hugh D.; Klein, David C.; Schnermann, Jürgen; Notkins, Abner Louis

doi:10.1096/fj.09-132019

Cited by 23 publications

(32 citation statements)

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“…Most notably in this context, loss of behavioral and physiological rhythms occurs only in mice with disruption of both genes (21). The single-KO mice have, at most, a subtle circadian phenotype (21).…”

Section: Peripheral Gene Expression Rhythms Are Relatively Unaffectedmentioning

confidence: 99%

“…A recent study to assess the cardiovascular impact of targeted disruption of IA-2 and IA-2␤ revealed that mice lacking these proteins did not have daily rhythms in blood pressure, heart rate, core body temperature, or spontaneous locomotor activity (21). Electrophysiological studies on the suprachiasmatic nuclei (SCN), the site of the brain's master circadian oscillator, showed that disruption of both IA-2 and IA-2␤ results in significant alterations in neuronal firing rhythms in the SCN (21).…”

mentioning

confidence: 99%

“…Electrophysiological studies on the suprachiasmatic nuclei (SCN), the site of the brain's master circadian oscillator, showed that disruption of both IA-2 and IA-2␤ results in significant alterations in neuronal firing rhythms in the SCN (21). Thus, disruption of IA-2 and IA-2␤ has a profound effect on the generation and expression of circadian rhythms.…”

mentioning

confidence: 99%

“…One hypothesis to explain the disruption of electrophysiological, physiological, and behavioral rhythms in doubleknockout (DKO) mice lacking IA-2 and IA-2␤ is that these proteins are critical for neurochemical interactions that couple SCN neurons to each other (21), as occurs in mice lacking vasoactive intestinal peptide (VIP) or the VPAC2 receptor (3, 5, 7, 8, 13, 15, 40; for review, see Ref. 52).…”

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Disruption of gene expression rhythms in mice lacking secretory vesicle proteins IA-2 and IA-2β

Punia

Rumery

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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Mice with targeted disruption of both IA-2 and IA-2␤ (double-knockout, or DKO mice) have numerous endocrine and physiological disruptions, including disruption of circadian and diurnal rhythms. In the present study, we have assessed the impact of disruption of IA-2 and IA-2␤ on molecular rhythms in the brain and peripheral oscillators. We used in situ hybridization to assess molecular rhythms in the hypothalamic suprachiasmatic nuclei (SCN) of wild-type (WT) and DKO mice. The results indicate significant disruption of molecular rhythmicity in the SCN, which serves as the central pacemaker regulating circadian behavior. We also used quantitative PCR to assess gene expression rhythms in peripheral tissues of DKO, single-knockout, and WT mice. The results indicate significant attenuation of gene expression rhythms in several peripheral tissues of DKO mice but not in either single knockout. To distinguish whether this reduction in rhythmicity reflects defective oscillatory function in peripheral tissues or lack of entrainment of peripheral tissues, animals were injected with dexamethasone daily for 15 days, and then molecular rhythms were assessed throughout the day after discontinuation of injections. Dexamethasone injections improved gene expression rhythms in liver and heart of DKO mice. These results are consistent with the hypothesis that peripheral tissues of DKO mice have a functioning circadian clockwork, but rhythmicity is greatly reduced in the absence of robust, rhythmic physiological signals originating from the SCN. Thus, IA-2 and IA-2␤ play an important role in the regulation of circadian rhythms, likely through their participation in neurochemical communication among SCN neurons. circadian; suprachiasmatic nucleus; vasoactive intestinal peptide; Prprn; Ptprn2 INSULINOMA-ASSOCIATED PROTEIN 2 (IA-2; also called islet antigen 2, ICA 512, and Prprn) and IA-2␤ (also called phogrin and Ptprn2) are transmembrane proteins with homology to protein tyrosine phosphatase but which lack phosphatase activity (29,35,36; for review, see Ref. 51). IA-2 and IA-2␤ are components of dense core vesicle membranes and play important roles in vesicle loading and release (11,14,17,29,44,49). Targeted disruption of these genes in mice leads to impaired secretion of hormones and neurotransmitters, which are more severe in mice lacking functional alleles of both genes (16, 22, 24 -26, 42, 48). These proteins are also of interest at the clinical level, since the majority of newly diagnosed diabetic patients have antibodies against these proteins, and antibodies appear years before disease development, identifying them as major autoantigens predictive of type 1 diabetes (30,36,49).A recent study to assess the cardiovascular impact of targeted disruption of IA-2 and IA-2␤ revealed that mice lacking these proteins did not have daily rhythms in blood pressure, heart rate, core body temperature, or spontaneous locomotor activity (21). Electrophysiological studies on the suprachiasmatic nuclei (SCN), the site of the brain's master cir...

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Section: Peripheral Gene Expression Rhythms Are Relatively Unaffectedmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Disruption of gene expression rhythms in mice lacking secretory vesicle proteins IA-2 and IA-2β

Punia

Rumery

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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“…Studies using genetic knockout mouse models have shown the involvement of IA-2 PTPs in secretory functions of pancreatic β-cells, the anterior pituitary, and learningrelated or circadian rhythm-related neuroendocrine cells (Kubosaki et al 2006;Mziaut et al 2008;Kim SM et al 2009;Nishimura et al 2009;Cai et al 2011). Recent molecular and cellular analyses have suggested that the IA-2 family of PTPs specifically contributes to exocytosis of SGs, SG stability, hormone sorting into SGs, and pancreatic β-cell growth Trajkovski et al 2008;Torii et al 2009;Saito et al 2011;Cai et al 2011).…”

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confidence: 99%

Immunohistochemical Analysis of IA-2 Family of Protein Tyrosine Phosphatases in Rat Gastrointestinal Endocrine Cells

Gomi

Kubota-Murata²,

Yasui

et al. 2012

J Histochem Cytochem.

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Islet-associated protein–2 (IA-2) and IA-2β (also known as phogrin) are unique neuroendocrine-specific protein tyrosine phosphatases (PTPs). The IA-2 family of PTPs was originally identified from insulinoma cells and discovered to be major autoantigens in type 1 diabetes. Despite its expression in the neural and canonical endocrine tissues, data on expression of the IA-2 family of PTPs in gastrointestinal endocrine cells (GECs) are limited. Therefore, we immunohistochemically investigated the expression of the IA-2 family of PTPs in the rat gastrointestinal tract. In the stomach, IA-2 and IA-2β were expressed in GECs that secrete serotonin, somatostatin, and cholecystokinin/gastrin-1. In addition to these hormones, secretin, gastric inhibitory polypeptide (also known as the glucose-dependent insulinotropic peptide), glucagon-like peptide-1, and glucagon, but not ghrelin were coexpressed with IA-2 or IA-2β in duodenal GECs. Pancreatic islet cells that secrete gut hormones expressed the IA-2 family of PTPs. The expression patterns of IA-2 and IA-2β were comparable. These results reveal that the IA-2 family of PTPs is expressed in a cell type–specific manner in rat GECs. The extensive expression of the IA-2 family of PTPs in pancreo-gastrointestinal endocrine cells and in the enteric plexus suggests their systemic contribution to nutritional control through a neuroendocrine signaling network.

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The Suprachiasmatic Nucleus (SCN)

2015

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

Cited by 23 publications

References 28 publications

Disruption of gene expression rhythms in mice lacking secretory vesicle proteins IA-2 and IA-2β

Disruption of gene expression rhythms in mice lacking secretory vesicle proteins IA-2 and IA-2β

Immunohistochemical Analysis of IA-2 Family of Protein Tyrosine Phosphatases in Rat Gastrointestinal Endocrine Cells

The Suprachiasmatic Nucleus (SCN)

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