Polycystin-1 and polycystin-2 are both required to amplify inositol-trisphosphate-induced Ca2+ release

Mekahli, Djalila; Sammels, Eva; Luyten, Tomas; Welkenhuyzen, Kirsten; Heuvel, L.P.W.J. van den; Levtchenko, Elena; Gijsbers, Rik; Bultynck, Geert; Parys, Jan B.; Smedt, Humbert De; Missiaen, Ludwig

doi:10.1016/j.ceca.2012.03.002

Cited by 44 publications

(42 citation statements)

References 40 publications

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“…[16][17][18][19][20][21] Precisely how intracellular calcium homeostasis is altered in ADPKD remains uncertain, because different experimental conditions have led to inconsistent results. 22 For example, experiments in which polycystin-1 is knocked down conclude that polycystin-1 amplifies IP3-induced calcium release, 23 whereas studies using heterologous overexpression of polycystin-1 reach the opposite conclusion. 9,10 Nevertheless, most studies that have measured resting intracellular calcium, endoplasmic reticulum calcium stores, and store-operated calcium entry in primary cell cultures or microdissected samples from human and rodent polycystic tissues have found them to be reduced (Table 1).…”

Section: Disruption Of Intracellular Calcium Homeostasis and Pkdmentioning

confidence: 99%

Strategies Targeting cAMP Signaling in the Treatment of Polycystic Kidney Disease

Torres

Harris

2014

Journal of the American Society of Nephrology

244

218

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Polycystic kidney disease (PKD) is a leading cause of ESRD worldwide. In PKD, excessive cell proliferation and fluid secretion, pathogenic interactions of mutated epithelial cells with an abnormal extracellular matrix and alternatively activated interstitial macrophages, and the disruption of mechanisms controlling tubular diameter contribute to cyst formation. Studies with animal models suggest that several diverse pathophysiologic mechanisms, including dysregulation of intracellular calcium levels and cAMP signaling, mediate these cystogenic mechanisms. This article reviews the evidence implicating calcium and cAMP as central players in a network of signaling pathways underlying the pathogenesis of PKD and considers the therapeutic relevance of treatment strategies targeting cAMP signaling.

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Section: Disruption Of Intracellular Calcium Homeostasis and Pkdmentioning

confidence: 99%

Strategies Targeting cAMP Signaling in the Treatment of Polycystic Kidney Disease

Torres

Harris

2014

Journal of the American Society of Nephrology

244

218

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“…It has been hypothesized that the disruption of PC2, or the proteins that it interacts with, will result in cyst growth, as Ca 2+ is a major signaling molecule (26,27). Cells with decreased PC2 have been linked with decreased Ca 2+ signaling (28), and overexpression of PC2 has been shown to act as an inhibitor of cell proliferation (29).…”

mentioning

confidence: 99%

Cyst formation following disruption of intracellular calcium signaling

Kuo¹,

DesRochers

Kimmerling

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Mutations in polycystin 1 and 2 (PC1 and PC2) cause the common genetic kidney disorder autosomal dominant polycystic kidney disease (ADPKD). It is unknown how these mutations result in renal cysts, but dysregulation of calcium (Ca 2+ ) signaling is a known consequence of PC2 mutations. PC2 functions as a Ca 2+ -activated Ca 2+ channel of the endoplasmic reticulum. We hypothesize that Ca 2+ signaling through PC2, or other intracellular Ca 2+ channels such as the inositol 1,4,5-trisphosphate receptor (InsP3R), is necessary to maintain renal epithelial cell function and that disruption of the Ca 2+ signaling leads to renal cyst development. The cell line LLC-PK1 has traditionally been used for studying PKD-causing mutations and Ca 2+ signaling in 2D culture systems. We demonstrate that this cell line can be used in long-term (8 wk) 3D tissue culture systems. In 2D systems, knockdown of InsP3R results in decreased Ca 2+ transient signals that are rescued by overexpression of PC2. In 3D systems, knockdown of either PC2 or InsP3R leads to cyst formation, but knockdown of InsP3R type 1 (InsP3R1) generated the largest cysts. InsP3R1 and InsP3R3 are differentially localized in both mouse and human kidney, suggesting that regional disruption of Ca 2+ signaling contributes to cystogenesis. All cysts had intact cilia 2 wk after starting 3D culture, but the cells with InsP3R1 knockdown lost cilia as the cysts grew. Studies combining 2D and 3D cell culture systems will assist in understanding how mutations in PC2 that confer altered Ca 2+ signaling lead to ADPKD cysts. primary cilia | polycysin 2 | calcium release T he commonly occurring genetic kidney disorder, autosomal dominant polycystic kidney disease (ADPKD), is the result of mutations in polycystin 1 or 2 (PC1 or PC2). The progressive cyst formation within all segments of the nephron that defines the disorder leads to renal failure requiring treatment by dialysis and/or organ transplantation (1-3). Altered Ca 2+ signaling is one of several pathways that have been implicated in the disease (4, 5). A major limitation toward elucidating the role of Ca 2+ signaling in cyst formation has been the lack of easily manipulated, physiologically relevant experimental methodologies.In the past, ADPKD research has relied largely upon data from mouse models and cells maintained in 2D cell culture. Mouse models have played a significant role in understanding the biology of cyst formation but are unable to fully recapitulate the physiology of disease progression in humans due to the inherent differences between the species including life span, genetics, and environment. Two-dimensional cell culture has the ability to provide information on signaling pathways and response to therapies in a fast, high-throughput manner, but is incapable of replicating the inherent 3D nature of cyst formation. Advances in 3D tissue culture over the past 2 decades have improved the ability to model cyst development in vitro. However, previously published 3D tissue models of ADPKD have relied upon shortter...

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“…Many of the above-mentioned results are challenged by data suggesting that polycystin 2 is acting as a Ca 2ϩ release channel situated on the ER (43). The function of polycystin 1 is apparently similarly essential to the function of polycystin 2 in the ER (56), where it interacts with the IP 3 receptor to manifest its effects (47,85). Since the cilium-dependent flow response in many cases has been shown be potentiated by downstream activation of IP 3 receptors/PKC activation (40,73) or ryanodine receptors (57), studies implicating polycystin 2 in the cilium-dependent flow response could be explained by polycystin 2 acting as a Ca 2ϩ -permeant channel on the ER.…”

Section: The Ciliary Channel Giving Rise To the Ciliary Ca 2ϩ Increasementioning

confidence: 77%

The primary cilium as sensor of fluid flow: new building blocks to the model. A Review in the Theme: Cell Signaling: Proteins, Pathways and Mechanisms

Praetorius

2015

American Journal of Physiology-Cell Physiology

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Polycystin-1 and polycystin-2 are both required to amplify inositol-trisphosphate-induced Ca2+ release

Cited by 44 publications

References 40 publications

Strategies Targeting cAMP Signaling in the Treatment of Polycystic Kidney Disease

Strategies Targeting cAMP Signaling in the Treatment of Polycystic Kidney Disease

Cyst formation following disruption of intracellular calcium signaling

The primary cilium as sensor of fluid flow: new building blocks to the model. A Review in the Theme: Cell Signaling: Proteins, Pathways and Mechanisms

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