Polycystin-2 is an intracellular calcium release channel

Koulen, Peter; Cai, Yiqiang; Geng, Lin; Maeda, Yoshiko; Nishimura, Sadako; Witzgall, Ralph; Ehrlich, Barbara E.; Somlo, Stefan

doi:10.1038/ncb754

Cited by 635 publications

(743 citation statements)

References 39 publications

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“…Nevertheless, it is possible that plasma membrane expression of PKD2 is not sufficient for function, but perhaps interactions with other subunits are needed for channel activity. It was subsequently shown that PKD2 functioned as a novel intracellular Ca 2+ channel which was activated in response to increases in intracellular Ca 2+ concentration [45]. Single channel studies indicated that ER-reconstituted PKD2 displayed channel activity and Ca 2+ imaging experiments revealed that PKD2 overexpression enhanced the amplitude and duration of G protein coupled receptor (GPCR) -induced Ca 2+ release transients in the kidney epithelial cell line, LLC-PK1 [45].…”

Section: Functional Compartmentalization Of Pkd2mentioning

confidence: 99%

“…It was subsequently shown that PKD2 functioned as a novel intracellular Ca 2+ channel which was activated in response to increases in intracellular Ca 2+ concentration [45]. Single channel studies indicated that ER-reconstituted PKD2 displayed channel activity and Ca 2+ imaging experiments revealed that PKD2 overexpression enhanced the amplitude and duration of G protein coupled receptor (GPCR) -induced Ca 2+ release transients in the kidney epithelial cell line, LLC-PK1 [45]. It was shown in the same study that PKD2 overexpression did not alter the Ca 2+ content of the intracellular stores as the response to the SERCA inhibitor, thapsigargin was identical between mock-and PKD2-transfected cells.…”

Section: Functional Compartmentalization Of Pkd2mentioning

confidence: 99%

“…While a structural or scaffolding role of pericentrin in centrosome and ciliary formation can be envisioned, it is difficult to predict a role of PKD2 as an ion channel in the centrosome. Nevertheless, given the role of PKD2 in intracellular Ca 2+ signaling [45], such a possibility remains an intriguing one.…”

Section: Function At the Primary Ciliummentioning

confidence: 99%

“…Overall, PKD2 activation has been shown to be induced by EGF [36], binding to PKD1 [35], and/or intracellular Ca 2+ [45]. Activation by EGF was described at the plasma membrane and is likely to also occur in the cilium because of the presence of some of the critical components there.…”

Section: Modes Of Pkd2 Activationmentioning

confidence: 99%

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Cell biology of polycystin-2

Tsiokas¹,

Kim²,

Ong³

2007

Cellular Signalling

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Naturally occurring mutations in two separate, but interacting loci, pkd1 and pkd2 are responsible for almost all cases of autosomal dominant polycystic kidney disease (ADPKD). ADPKD is one of the most common genetic diseases resulting primarily in the formation of large kidney, liver, and pancreatic cysts. Homozygous deletion of either pkd1 or pkd2 results in embryonic lethality in mice due to kidney and heart defects illustrating their indispensable roles in mammalian development. However, the mechanism by which mutations in these genes cause ADPKD and other developmental defects are unknown. Research in the past several years has revealed that PKD2 has multiple functions depending on its subcellular localization. It forms a receptor-operated, non-selective cation channel in the plasma membrane, a novel intracellular Ca 2+ release channel in the endoplasmic reticulum (ER), and a mechanosensitive channel in the primary cilium. This review focuses on the functional compartmentalization of PKD2, its modes of activation, and PKD2-mediated signal transduction.

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Section: Functional Compartmentalization Of Pkd2mentioning

confidence: 99%

Section: Functional Compartmentalization Of Pkd2mentioning

confidence: 99%

Section: Function At the Primary Ciliummentioning

confidence: 99%

Section: Modes Of Pkd2 Activationmentioning

confidence: 99%

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Cell biology of polycystin-2

Tsiokas¹,

Kim²,

Ong³

2007

Cellular Signalling

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“…These include the basolateral plasma membrane of epithelial cells [64]; the endoplasmic reticulum This is the Pre-Published Version (ER) where it may operate as a Ca 2+ -release channel [65], and the primary cilia where it is thought to participate in mechanosensation [66]. The function of TRPP2 in primary cilia has been linked to the formation of kidney cysts in vertebrates.…”

Section: Trp Channels Are Involved In the Generation Of The Ca 2+ Sigmentioning

confidence: 99%

Ca2+ coding and decoding strategies for the specification of neural and renal precursor cells during development

et al. 2016

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Autosomal Dominant Polycystic Kidney Disease

Arnaout

2010

Encyclopedia of Life Sciences

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Autosomal dominant polycystic disease (ADPKD) is the most common monogenic disease in humans and is among the leading causes of kidney failure. Dominantly inherited germline mutations in 2 genes, PKD1 and PKD2 followed by a second somatic hit that annuls or reduces the function of the remaining normal allele lead to loss of tube diameter control, cyst formation and eventual kidney failure. The respective gene products, polycystin‐1 and polycystin‐2 form a receptor–ion channel complex that transduces mechanical and/or chemical signals into a calcium entry signal that regulates cell polarity, proliferation and movement. Localisation of this complex in the primary cilium has linked this sensory organelle to the regulation of tube size. Here we review the recent advances made in elucidating pathogenesis, diagnosis and management of this disease and the experimental therapies targeting the implicated signalling pathways. Key Concepts: ADPKD presents with tubular dilatations/cysts mainly affecting the kidney, liver and cardiovascular system, reflecting a defect in tube diameter control. Arterial hypertension is common and occurs early. Current therapy is largely conservative. ADPKD is caused by commonly inactivating germline mutations in PKD1 or PKD2 combined with a second somatic hit that abolishes or reduces function of the remaining normal allele, an event enhanced by the genomic instability associated with the haploid state. Wide variations in onset and progression of the disease are caused by the type of the impaired gene, hypomorphic alleles, mosaicism, combining an inactivating germline mutation with an acquired hypomorphic allele, stochastic fluctuations in expression level of the remaining normal allele and the genetic background. Cerebral aneurysms are more common in ADPKD patients, occur at an earlier age and tend to rupture at a smaller size when compared to the general population. Progressive loss of renal function occurs before standard markers of renal function are abnormal. Measurement of kidney volume in patients with normal renal function using MR imaging (MRI), CT, or ultrasonography is a more sensitive approach for following disease progression at any age. DNA‐based diagnostics are useful when imaging studies are equivocal, in individuals with a negative family history, in the selection of a young transplant donor from an ADPKD family or to facilitate pre‐implantation genetic diagnosis. The gene products of PKD1 and PKD2 , polyctytsin‐1 (PC1) and polycystin‐2 (PC2), respectively, localise to primary cilia as well as to other membrane compartments. Defects in primary cilium structure causes cysts, as are mutations in several other ciliogenic genes supporting a critical role of the primary cilium in tube formation and maintenance. PC1 and PC2 form a receptor‐ion channel complex that triggers calcium entry, which normally activates the planar polarity pathway and represses mitogenic pathways thus regulating tube diameter. The abnormal mitogenesis and fluid secretion pathways that contribute to cyst growth are being targeted therapeutically.

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Polycystin-2 is an intracellular calcium release channel

Cited by 635 publications

References 39 publications

Cell biology of polycystin-2

Cell biology of polycystin-2

Ca2+ coding and decoding strategies for the specification of neural and renal precursor cells during development

Autosomal Dominant Polycystic Kidney Disease

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