Inhibition of CN (protein phosphatase‐2B) suppresses Ca<sup>2+</sup>‐mediated acid secretion in rats

Itoh, Satoshi; Otaka, Michiro; Odashima, Masaru; Zeniya, Akira; Okuyama, Atsushi; Jin, Mario; Otani, Setsuya; Iwabuchi, A.; Sasahara, Hideaki; Masamune, Osamu; Watanabe, Sumio

doi:10.1046/j.1365-2036.16.s2.7.x

Cited by 5 publications

(1 citation statement)

References 31 publications

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“…In the gastrointestinal tract, calcineurin signaling is involved in the regulation of secretory processes. In gastric chief cells, calcineurin is responsible for pepsinogen release; in gastric parietal cells, it is responsible for gastric acid secretion [ 92 , 93 ].…”

Section: General Calcineurin Functionmentioning

confidence: 99%

Calcineurin Is a Universal Regulator of Vessel Function—Focus on Vascular Smooth Muscle Cells

Nolze,

Matern,

Grossmann

2023

Cells

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Calcineurin, a serine/threonine phosphatase regulating transcription factors like NFaT and CREB, is well known for its immune modulatory effects and role in cardiac hypertrophy. Results from experiments with calcineurin knockout animals and calcineurin inhibitors indicate that calcineurin also plays a crucial role in vascular function, especially in vascular smooth muscle cells (VSMCs). In the aorta, calcineurin stimulates the proliferation and migration of VSMCs in response to vascular injury or angiotensin II administration, leading to pathological vessel wall thickening. In the heart, calcineurin mediates coronary artery formation and VSMC differentiation, which are crucial for proper heart development. In pulmonary VSMCs, calcineurin/NFaT signaling regulates the release of Ca2+, resulting in increased vascular tone followed by pulmonary arterial hypertension. In renal VSMCs, calcineurin regulates extracellular matrix secretion promoting fibrosis development. In the mesenteric and cerebral arteries, calcineurin mediates a phenotypic switch of VSMCs leading to altered cell function. Gaining deeper insights into the underlying mechanisms of calcineurin signaling will help researchers to understand developmental and pathogenetical aspects of the vasculature. In this review, we provide an overview of the physiological function and pathophysiology of calcineurin in the vascular system with a focus on vascular smooth muscle cells in different organs. Overall, there are indications that under certain pathological settings reduced calcineurin activity seems to be beneficial for cardiovascular health.

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Section: General Calcineurin Functionmentioning

confidence: 99%

Calcineurin Is a Universal Regulator of Vessel Function—Focus on Vascular Smooth Muscle Cells

Nolze,

Matern,

Grossmann

2023

Cells

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Functional partitioning of epithelial protein kinase CaMKII in signal transduction

Fährmann

Kaufhold

2006

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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The examination of the physiological role of CaMKII has made substantial progress in non-epithelial systems but little is known about its function in secretory epithelial cells. A prototypic exocrine cell, the acid secreting gastric parietal cell, largely redistributes its cytoplasmic tubulocisternal membranes (TC) to the secretory apical membrane (SA) after stimulation. We here present a dependence of physiological response on partitioned initial CaMKII activities redistributed between TC and SA. Initial acid secretion after cholinergic stimulation has doubled if activities of phosphatases PP1/PP2A and protein kinase PKC-alpha were inhibited by the inhibitors calyculin A and Gö 6976. CaMKII appears to be integrated in multienzyme complexes each specific for TC and SA. Therein, PP1/PP2A and PKC-alpha were found to permanently counteract initial CaMKII activities in different modes of transregulation. Remarkably, a dys-transregulated, hyperactive CaMKII at TC did not result in an increased acid secretion to the same extent. A simple mathematical model to estimate the share of TC- and SA-associated CaMKII activities in cholinergically induced acid secretion suggests that TC-associated CaMKII appears to autoregulate its contribution to the physiological response by a negative feedback control. Subcellular distribution and stimulus-dependent redistribution of domain-associated CaMKII signalosomes indicate a fine balanced, adaptive system to guarantee a stable physiological response.

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Stringent time-dependent transregulation of calcium calmodulin kinase II (CaMKII) is implicated in anti-apoptotic control

Fährmann

Honisch

Kaufhold

et al. 2008

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Induction of apoptosis by the PP1/PP2A inhibitor calyculin A was inhibited if the CaMKII inhibitor KN-93 was added no later than 10 min after addition of calyculin A. The physiological relevance and mechanism of CaMKII during apoptosis, however, remains largely unclear. Here we show in MDCK and gastric parietal cells that normal transregulation of CaMKII terminates the initial burst of autophosphorylation after only 10 min. The kinetics of CaMKII involved transregulation by PP1, PP2A, PP2B and PKCalpha. Transregulation of CaMKII resulted in two kinetic phases for phosphorylation of the autoactivation site at T286/287. During the initial phase, there was a clear peak of phosphorylation that lasted 10 min. This phase was subsequently followed by a half but constant level of T286/287 phosphorylation. Calyculin A perturbed this transregulation, resulting in a hyperphosphorylated CaMKII. This effect of CA on the kinetics of CaMKII was observed in vivo as well as in vitro using isolated tubulovesicles. Calyculin A-induced hyperphosphorylation of CaMKII appears to be at least one mechanism used by cells to trigger apoptosis. Therefore, stringent limitation of CaMKII autophosphorylation at T286/287 by transregulation and prevention of hyperphosphorylation seems to restrict apoptosis.

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Inhibition of CN (protein phosphatase‐2B) suppresses Ca²⁺‐mediated acid secretion in rats

Cited by 5 publications

References 31 publications

Calcineurin Is a Universal Regulator of Vessel Function—Focus on Vascular Smooth Muscle Cells

Calcineurin Is a Universal Regulator of Vessel Function—Focus on Vascular Smooth Muscle Cells

Functional partitioning of epithelial protein kinase CaMKII in signal transduction

Stringent time-dependent transregulation of calcium calmodulin kinase II (CaMKII) is implicated in anti-apoptotic control

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Inhibition of CN (protein phosphatase‐2B) suppresses Ca2+‐mediated acid secretion in rats

Cited by 5 publications

References 31 publications

Calcineurin Is a Universal Regulator of Vessel Function—Focus on Vascular Smooth Muscle Cells

Calcineurin Is a Universal Regulator of Vessel Function—Focus on Vascular Smooth Muscle Cells

Functional partitioning of epithelial protein kinase CaMKII in signal transduction

Stringent time-dependent transregulation of calcium calmodulin kinase II (CaMKII) is implicated in anti-apoptotic control

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Inhibition of CN (protein phosphatase‐2B) suppresses Ca²⁺‐mediated acid secretion in rats