Calcineurin upregulates local Ca<sup>2+</sup>signaling through ryanodine receptor-1 in airway smooth muscle cells

Savoia, Carlo; Liu, Qinghua; Zheng, Yun‐Min; Yadav, Vishal; Zhang, Zhen; Wu, Ling−Gang; Wang, Yong-Xiao

doi:10.1152/ajplung.00149.2014

Cited by 10 publications

(7 citation statements)

References 52 publications

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“…Moreover, CaN inhibitors (CsA and FK506) can modify RyR2 function, as Bandyopadhyay et al report they can reduce the frequency of spark calcium release [ 94 ]. This data is further supported by Savoia et al as they demonstrated in 2014 that application of a CaN autoinhibitory peptide reduces RyR2 calcium release frequency in airway smooth muscle cells [ 105 ].…”

Section: An Overview Of Calcineurin Function In Cardiac Physiologysupporting

confidence: 53%

A Review of Calcineurin Biophysics with Implications for Cardiac Physiology

Williams

Johnson

2021

IJMS

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Calcineurin, also known as protein phosphatase 2B, is a heterodimeric serine threonine phosphatase involved in numerous signaling pathways. During the past 50 years, calcineurin has been the subject of extensive investigation. Many of its cellular and physiological functions have been described, and the underlying biophysical mechanisms are the subject of active investigation. With the abundance of techniques and experimental designs utilized to study calcineurin and its numerous substrates, it is difficult to reconcile the available information. There have been a plethora of reports describing the role of calcineurin in cardiac disease. However, a physiological role of calcineurin in healthy cardiomyocyte function requires clarification. Here, we review the seminal biophysical and structural details that are responsible for the molecular function and inhibition of calcineurin. We then focus on literature describing the roles of calcineurin in cardiomyocyte physiology and disease.

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Section: An Overview Of Calcineurin Function In Cardiac Physiologysupporting

confidence: 53%

A Review of Calcineurin Biophysics with Implications for Cardiac Physiology

Williams

Johnson

2021

IJMS

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“…To determine whether activation of calcineurin is protective, we treated HEK293 cells with the metal ion Ni 2+ . Ni 2+ is a robust calmodulin-independent activator of calcineurin in vitro and in vivo [28, 48, 51]. Incubating HEK293 cells with Ni 2+ treatment resulted in clearance of pTDP-35 (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

The phosphatase calcineurin regulates pathological TDP-43 phosphorylation

et al. 2016

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Detergent insoluble inclusions of TDP-43 protein are hallmarks of the neuropathology in over 90% of amyotrophic lateral sclerosis (ALS) cases and approximately half of frontotemporal dementia (FTLD-TDP) cases. In TDP-43 proteinopathy disorders, lesions containing aggregated TDP-43 protein are extensively post-translationally modified, with phosphorylated TDP-43 (pTDP) being the most consistent and robust marker of pathological TDP-43 deposition. Abnormally phosphorylated TDP-43 has been hypothesized to mediate TDP-43 toxicity in many neurodegenerative disease models. To date several different kinases have been implicated in the genesis of pTDP, but no phosphatases have been shown to reverse pathological TDP-43 phosphorylation. We have identified the phosphatase calcineurin as an enzyme binding to and catalyzing the removal of pathological C-terminal phosphorylation of TDP-43 in vitro. In C. elegans models of TDP-43 proteinopathy, genetic elimination of calcineurin results in accumulation of excess pTDP, exacerbated motor dysfunction, and accelerated neurodegenerative changes. In cultured human cells, treatment with FK506 (tacrolimus), a calcineurin inhibitor, results in accumulation of pTDP species. Lastly, calcineurin co-localizes with pTDP in degenerating areas of the central nervous system in subjects with FTLD-TDP and ALS. Taken together these findings suggest calcineurin acts on pTDP as a phosphatase in neurons. Furthermore, patient treatment with calcineurin inhibitors may have unappreciated adverse neuropathological consequences.

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“…However, in SMCs, some studies suggest that calcineurin does not modulate RyR function (922, 924, 925). In contrast, inhibition of calcineurin or its genetic knockout inhibits RyR1 function in murine airway smooth SMCs (1256). Thus, there may be regional or species differences in the role played by calcineurin in the modulation of SMC RyR function.…”

Section: Ryanodine Receptorsmentioning

confidence: 99%

Smooth Muscle Ion Channels and Regulation of Vascular Tone in Resistance Arteries and Arterioles

Tykocki

Boerman

Jackson

2017

Comprehensive Physiology

282

347

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Vascular tone of resistance arteries and arterioles determines peripheral vascular resistance, contributing to the regulation of blood pressure and blood flow to, and within the body’s tissues and organs. Ion channels in the plasma membrane and endoplasmic reticulum of vascular smooth muscle cells (SMCs) in these blood vessels importantly contribute to the regulation of intracellular Ca2+ concentration, the primary determinant of SMC contractile activity and vascular tone. Ion channels provide the main source of activator Ca2+ that determines vascular tone, and strongly contribute to setting and regulating membrane potential, which, in turn, regulates the open-state-probability of voltage gated Ca2+ channels (VGCCs), the primary source of Ca2+ in resistance artery and arteriolar SMCs. Ion channel function is also modulated by vasoconstrictors and vasodilators, contributing to all aspects of the regulation of vascular tone. This review will focus on the physiology of VGCCs, voltage-gated K+ (KV) channels, large-conductance Ca2+-activated K+ (BKCa) channels, strong-inward-rectifier K+ (KIR) channels, ATP-sensitive K+ (KATP) channels, ryanodine receptors (RyRs), inositol 1,4,5-trisphosphate receptors (IP3Rs), and a variety of transient receptor potential (TRP) channels that contribute to pressure-induced myogenic tone in resistance arteries and arterioles, the modulation of the function of these ion channels by vasoconstrictors and vasodilators, their role in the functional regulation of tissue blood flow and their dysfunction in diseases such as hypertension, obesity, and diabetes.

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Calcineurin upregulates local Ca²⁺signaling through ryanodine receptor-1 in airway smooth muscle cells

Abstract: . Calcineurin upregulates local Ca 2ϩ signaling through ryanodine receptor-1 in airway smooth muscle cells.

Cited by 10 publications

References 52 publications

A Review of Calcineurin Biophysics with Implications for Cardiac Physiology

A Review of Calcineurin Biophysics with Implications for Cardiac Physiology

The phosphatase calcineurin regulates pathological TDP-43 phosphorylation

Smooth Muscle Ion Channels and Regulation of Vascular Tone in Resistance Arteries and Arterioles

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Calcineurin upregulates local Ca2+signaling through ryanodine receptor-1 in airway smooth muscle cells

Abstract: . Calcineurin upregulates local Ca 2ϩ signaling through ryanodine receptor-1 in airway smooth muscle cells.

Cited by 10 publications

References 52 publications

A Review of Calcineurin Biophysics with Implications for Cardiac Physiology

A Review of Calcineurin Biophysics with Implications for Cardiac Physiology

The phosphatase calcineurin regulates pathological TDP-43 phosphorylation

Smooth Muscle Ion Channels and Regulation of Vascular Tone in Resistance Arteries and Arterioles

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Calcineurin upregulates local Ca²⁺signaling through ryanodine receptor-1 in airway smooth muscle cells