Heterologous expression of polycystin-1 inhibits endoplasmic reticulum calcium leak in stably transfected MDCK cells

Weber, Kimberly H.; Lee, Eun Kyung; Basavanna, Uma; Lindley, Sabina; Ziegelstein, Roy C.; Germino, Gregory G.; Sutters, Michael

doi:10.1152/ajprenal.00348.2007

Cited by 22 publications

(18 citation statements)

References 38 publications

(37 reference statements)

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“…release is altered depending upon whether STIM1 or PC2 is associated with the IP 3 R Since PC1 affects interaction of PC2 and IP 3 R, we then asked whether it also affects release of Ca with Mag-Fura 2 by this group did not show any difference in ER Ca 2+ level despite a change in the leak rate [35]. In line with their result, the response to ionomycin was similar in control and PC1-expressing cells ( sup.…”

Section: +supporting

confidence: 72%

Polycystin-1, 2, and STIM1 Interact with IP3R to Modulate ER Ca2+ Release through the PI3K/Akt Pathway

Santoso

Cebotaru

Guggino

2011

Cell Physiol Biochem

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Dysregulation of Ca²⁺ signaling and homeostasis has been linked to the development of ADPKD through aberrant functioning of the polycystins. In this study, we investigated the role of the polycystins in modulating Ca²⁺ signaling. Expression of full-length PC1 in MDCK cells inhibited intracellular Ca²⁺ release in response to ATP when compared to control cells. This phenotype correlated with reduced interaction of endogenous PC2 and IP₃R in PC1-containing cells. We also found that endogenous STIM1 also interacted with the IP₃R, and this interaction was enhanced by PC1 expression. Increased interaction between STIM1 and IP₃R inhibited Ca²⁺ release. PC1 regulates intracellular Ca²⁺ release and the interaction of PC2-IP₃R-STIM1 through the PI3K/Akt signaling pathway. Inhibition of the PI3K/Akt pathway in PC1 containing cells restored intracellular Ca²⁺ release, increased the interaction between PC2 and IP₃R and disrupted the STIM1-IP₃R complex. Conversely, activation of the PI3K/Akt signaling pathway by HGF in control MDCK cells gave the reverse effects. It reduced the release of Ca²⁺ to levels comparable to the PC1 cells, inhibited the association PC2 and IP₃R, and increased the interaction between STIM and IP₃R. Overall, our studies provide a potential mechanism for the modulation of intracellular Ca²⁺ signaling by the polycystins.

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Section: +supporting

confidence: 72%

Polycystin-1, 2, and STIM1 Interact with IP3R to Modulate ER Ca2+ Release through the PI3K/Akt Pathway

Santoso

Cebotaru

Guggino

2011

Cell Physiol Biochem

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“…7). Both polycystin1 and polycystin2 are known to be required to maintain proper ER lumenal calcium levels (Koulen et al, 2002;Grimm et al, 2003;Nauli et al, 2003;Qian et al, 2003b;Qian et al, 2003a;Hooper et al, 2005;Anyatonwu et al, 2007;Xu et al, 2007;Weber et al, 2008). It is possible that, in addition to a role as a matrix sensor, polycystin maintenance of ER calcium may also be required for proper collagen crosslinking and assembly.…”

Section: Research Articlementioning

confidence: 99%

The ADPKD genespkd1a/bandpkd2regulate extracellular matrix formation

Mangos

Lam

Zhao

et al. 2010

Disease Models &Amp; Mechanisms

125

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SUMMARYMutations in polycystin1 (PKD1) account for the majority of autosomal dominant polycystic kidney disease (ADPKD). PKD1 mutations are also associated with vascular aneurysm and abdominal wall hernia, suggesting a role for polycystin1 in extracellular matrix (ECM) integrity. In zebrafish, combined knockdown of the PKD1 paralogs pkd1a and pkd1b resulted in dorsal axis curvature, hydrocephalus, cartilage and craniofacial defects, and pronephric cyst formation at low frequency (10-15%). Dorsal axis curvature was identical to the axis defects observed in pkd2 knockdown embryos. Combined pkd1a/b, pkd2 knockdown demonstrated that these genes interact in axial morphogenesis. Dorsal axis curvature was linked to notochord collagen overexpression and could be reversed by knockdown of col2a1 mRNA or chemical inhibition of collagen crosslinking. pkd1a/b-and pkd2-deficient embryos exhibited ectopic, persistent expression of multiple collagen mRNAs, suggesting a loss of negative feedback signaling that normally limits collagen gene expression. Knockdown of pkd1a/b also dramatically sensitized embryos to low doses of collagen-crosslinking inhibitors, implicating polycystins directly in the modulation of collagen expression or assembly. Embryos treated with wortmannin or LY-29400 also exhibited dysregulation of col2a1 expression, implicating phosphoinositide 3-kinase (PI3K) in the negative feedback signaling pathway controlling matrix gene expression. Our results suggest that pkd1a/b and pkd2 interact to regulate ECM secretion or assembly, and that altered matrix integrity may be a primary defect underlying ADPKD tissue pathologies.

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“…60 In another study PC1 was shown to inhibit calcium leak across the endoplasmic reticulum membrane. 58 More recently PC1 has been proposed to play a more complex role in the regulation of calcium release from the endoplasmic reticulum through its interactions with PC2 and STIM1. 33 Exogenous expression of PC1 reduces the interaction of IP3R with PC2 and enhances the interaction of STIM1 with IP3R leading to inhibition of endoplasmic reticulum calcium release, enhancement of PC2 traffic to the plasma membrane and entry of extracellular calcium, and inhibition of store operated calcium entry.…”

Section: Introductionmentioning

confidence: 99%

“…34,58 Either loss or gain of function may disrupt the physiological role of the polycystins and lead to a cystic phenotype. 11,72–75 …”

Section: Introductionmentioning

confidence: 99%

Vasopressin and disruption of calcium signalling in polycystic kidney disease

et al. 2015

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Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common monogenic kidney disease and the fourth leading cause of end-stage renal disease, responsible for 5–10% of cases. The disease is characterized by relentless development and growth of cysts causing progressive kidney enlargement associated with hypertension, pain, reduced quality of life, and eventually kidney failure. It is caused by mutations to PKD1 or PKD2, encoding polycystin-1 and polycystin-2, respectively. Their function and the molecular mechanisms responsible for the development of polycystic kidney disease are not well understood. The objective of this review is to synthesize a large body of literature that examines how reduction of functional PC1 or PC2 at the primary cilia and/or the endoplasmic reticulum directly disrupts intracellular calcium signaling and indirectly disrupts calcium regulated cAMP and purinergic signaling. We propose a hypothetical model where dysregulated metabolism of cAMP and purinergic signaling increase the sensitivity of principal cells in collecting ducts and of tubular epithelial cells in the distal nephron to the constant tonic action of vasopressin. The resulting magnified response to vasopressin further enhances the disruption of calcium signaling initiated by mutations to PC1 or PC2 and activates downstream signaling pathways responsible for impaired tubulogenesis, cell proliferation, increased fluid secretion and interstitial inflammation.

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Heterologous expression of polycystin-1 inhibits endoplasmic reticulum calcium leak in stably transfected MDCK cells

Cited by 22 publications

References 38 publications

Polycystin-1, 2, and STIM1 Interact with IP<sub>3</sub>R to Modulate ER Ca<sup>2+</sup> Release through the PI3K/Akt Pathway

Polycystin-1, 2, and STIM1 Interact with IP<sub>3</sub>R to Modulate ER Ca<sup>2+</sup> Release through the PI3K/Akt Pathway

The ADPKD genespkd1a/bandpkd2regulate extracellular matrix formation

Vasopressin and disruption of calcium signalling in polycystic kidney disease

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