Polycystin-L is a calcium-regulated cation channel permeable to calcium ions

Chen, Xing Zhen; Vassilev, Peter; Basora, Nùria; Ji, Peng; Nomura, Hideki; Segal, Yoav; Brown, Edward M.; Reeders, Stephen T.; Hediger, Matthias A.; Zhou, Jing

doi:10.1038/43907

Cited by 161 publications

(196 citation statements)

References 29 publications

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“…As concerns pharmacologic profile of I CC , although qualitatively consistent with PC2 sensitivity (9,10,36,42), it must be noted that amiloride, La 3ϩ , Gd 3ϩ , and Ni 2ϩ lack specificity, blocking various channels and transporters. The dose-response relation of the effect of amiloride on I CC (data not shown) gave a half-maximum inhibition at 245 M, slightly higher than that reported for native PC2 (36).…”

Section: Discussionmentioning

confidence: 99%

Nonspecific Cation Current Associated with Native Polycystin-2 in HEK-293 Cells

Pelucchi¹,

Aguiari²,

Pignatelli³

et al. 2006

Journal of the American Society of Nephrology

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Mutations in either PKD1 or PKD2 gene are associated with autosomal dominant polycystic kidney disease, the most common inherited kidney disorder. Polycystin-2 (PC2), the PKD2 gene product, and the related protein polycystin-L, function as Ca 2؉ -permeable, nonselective cation channels in different expression systems. This work describes a nonspecific cation current (I CC ) that is present in native HEK-293 cells and highly associated with a PC2-channel activity. The current is voltage dependent, activating for potentials that are positive to ؊50 mV and inactivating in a few milliseconds. It is sensitive to Cd 2؉ , Gd 3؉ , La 3؉ , SKF96365, and amiloride. After silencing of PC2 by RNA interfering, cells show a reduced current that is restored by transfection with normal but not truncated PC2. Consistently, I CC is abolished by perfusion with an anti-PC2 antibody. Furthermore, heterologous expression of the PC1 cytoplasmic tail significantly increases I CC peak amplitude compared with native cells. This is the first characterization of such a current in HEK-293 cells, a widely used expression system for ion channels. These cells, therefore, could be regarded as a suitable and readily accessible tool to study interactions between native PC2/PC1 complex and other membrane proteins, thus contributing to the understanding of autosomal dominant polycystic kidney disease pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Nonspecific Cation Current Associated with Native Polycystin-2 in HEK-293 Cells

Pelucchi¹,

Aguiari²,

Pignatelli³

et al. 2006

Journal of the American Society of Nephrology

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“…45 Ca Uptake-Radiotracer uptake experiments were performed as described previously (15). In brief, radioactive 45 CaCl 2 (Amersham Biosciences, UK) at 30 M was added to the uptake solution (100 mM N-methyl-D-glucamine, 2 mM KCl, 1 mM MgCl 2 , 10 mM HEPES, pH 7.5) plus 1 mM non-radioactive CaCl 2 .…”

Section: Methodsmentioning

confidence: 99%

“…In Xenopus laevis oocytes, TRPP3 targets to the plasma membrane when expressed alone and acts as a Ca 2ϩ -activated channel permeable to Na ϩ , K ϩ , and Ca 2ϩ (15,16). In human embryonic kidney (HEK) cell lines, TRPP3 mainly targets to the endoplasmic reticulum membrane when expressed alone but traffics to the plasma membrane when co-expressed with PKD1 or PKD1L3, a homologue of PKD1 (9,17,18).…”

mentioning

confidence: 99%

Regulation of TRPP3 Channel Function by N-terminal Domain Palmitoylation and Phosphorylation

Zheng¹,

Yang²,

Beauchamp

et al. 2016

Journal of Biological Chemistry

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Edited by Roger ColbranTransient receptor potential polycystin-3 (TRPP3) is a cation channel activated by calcium and proton and is involved in hedgehog signaling, intestinal development, and sour tasting. How TRPP3 channel function is regulated remains poorly understood. By N-terminal truncation mutations, electrophysiology, and Xenopus oocyte expression, we first identified fragment Asp-21-Ser-42 to be functionally important. We then found that deletion mutant ⌬1-36 (TRPP3 missing fragment Met-1-Arg-36) has a similar function as wild-type TRPP3, whereas ⌬1-38 is functionally dead, suggesting the importance of Val-37 or Cys-38. Further studies found that Cys-38, but not Val-37, is functionally critical. Cys-38 is a predicted site of palmitoylation, and indeed TRPP3 channel activity was inhibited by palmitoylation inhibitor 2-bromopalmitate and rescued by palmitoylation substrate palmitic acid. The TRPP3 N terminus (TRPP3NT, Met-1-Leu-95) localized along the plasma membrane of HEK293 cells but stayed in the cytoplasm with 2-bromopalmitate treatment or C38A mutation, indicating that TRPP3NT anchors to the surface membrane through palmitoylation at Cys-38. By acyl-biotin exchange assays, we showed that TRPP3, but not mutant C38A, is indeed palmitoylated. When putative phosphorylation sites near Cys-38 were mutated to Asp or Glu to mimic phosphorylation, only T39D and T39E reduced TRPP3 function. Furthermore, TRPP3NT displayed double bands in which the upper band was abolished by phosphatase treatment or T39A mutation. However, palmitoylation at Cys-38 and phosphorylation at Thr-39 independently regulated TRPP3 channel function, in contrast to previous reports about correlated palmitoylation with a proximate phosphorylation. Palmitoylation at Cys-38 represents a novel mechanism of functional regulation for TRPP3.

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“…Polycystin-2 is a distant member of the transient receptor potential (TRP) family of ion channels, TRPP2 (Figure 1). 10,35,36 As with other TRP channels, it has six transmembrane domains and is thought to act as a homo-or heterotetramer. It is a nonselective cation channel that transports Ca 2ϩ and is modulated by intracellular Ca 2ϩ levels.…”

Section: Adpkd Proteins Polycystin-1 and ؊2mentioning

confidence: 99%

2008 Homer W. Smith Award

Harris

2009

Journal of the American Society of Nephrology

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Polycystin-L is a calcium-regulated cation channel permeable to calcium ions

Cited by 161 publications

References 29 publications

Nonspecific Cation Current Associated with Native Polycystin-2 in HEK-293 Cells

Nonspecific Cation Current Associated with Native Polycystin-2 in HEK-293 Cells

Regulation of TRPP3 Channel Function by N-terminal Domain Palmitoylation and Phosphorylation

2008 Homer W. Smith Award

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