Disrupting polycystin-2 EF hand Ca2+ affinity does not alter channel function or contribute to polycystic kidney disease

Vien, Thuy N.; Ng, Leo C.T.; Smith, Jessica M.; Dong, Ke; Krappitz, Matteus; Gainullin, Vladimir G.; Fedeles, Sorin V.; Harris, Peter C.; Somlo, Stefan; DeCaen, Paul G.

doi:10.1242/jcs.255562

Cited by 10 publications

(13 citation statements)

References 72 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In a limiting case, a single PC2 channel was able to conduct enough Ca 2+ into the cilium to further activate itself ( Figures 1B, C , 2B,C , 3B , 4B ). This presumably requires diffusion of Ca 2+ over a very short distance, from the mouth of the channel pore to an internal Ca 2+ -activation site on the same channel, which has not been identified ( Vien et al, 2020 ). This self-activation was somewhat more effective with EGTA than with BAPTA ( Figures 3 , 4 ).…”

Section: Discussionmentioning

confidence: 99%

Regenerative Calcium Currents in Renal Primary Cilia

Kleene

2022

Front. Physiol.

View full text Add to dashboard Cite

Polycystic kidney disease (PKD) is a leading cause of end-stage renal disease. PKD arises from mutations in proteins, one a Ca2+-conducting channel, expressed in the primary cilia of renal epithelial cells. A common hypothesis is that Ca2+ entering through ciliary ion channels may reduce cystogenesis. The cilia have at least two Ca2+-conducting channels: polycystin-2 (PC2) and TRPV4 (transient receptor potential (TRP) cation channel, subfamily V, member 4), but how substantially they can increase intraciliary Ca2+ is unknown. By recording channel activities in isolated cilia, conditions are identified under which the channels can increase free Ca2+ within the cilium by at least 500-fold through regenerative (positive-feedback) signaling. Ca2+ that has entered through a channel can activate the channel internally, which increases the Ca2+ influx, and so on. Regenerative signaling is favored when the concentration of the Ca2+ buffer is reduced or when a slower buffer is used. Under such conditions, the Ca2+ that enters the cilium through a single PC2 channel is sufficient to almost fully activate that same channel. Regenerative signaling is not detectable with reduced external Ca2+. Reduced buffering also allows regenerative signaling through TRPV4 channels, but not through TRPM4 (TRP subfamily M, member 4) channels, which are activated by Ca2+ but do not conduct it. On a larger scale, Ca2+ that enters through TRPV4 channels can cause secondary activation of PC2 channels. I discuss the likelihood of regenerative ciliary Ca2+ signaling in vivo, a possible mechanism for its activation, and how it might relate to cystogenesis.

show abstract

Section: Discussionmentioning

confidence: 99%

Regenerative Calcium Currents in Renal Primary Cilia

Kleene

2022

Front. Physiol.

View full text Add to dashboard Cite

show abstract

“…The PKD2 C-terminal EF-hand motif (H750-E785) was proposed to act as a Ca 2+ sensor required for channel gating ( Figure 1 ) ( Ćelić et al, 2012 ), which is consistent with the observation that pathogenic mutant L703X missing the EF-hand exhibits no sensitivity to Ca 2+ ( Koulen et al, 2002 ). However, study using direct patch clamping in primary cilia and knock-in mouse models found that loss of Ca 2+ /EF-hand binding does not significantly alter the channel function or result in cyst formation, and thus proposed that a Ca 2+ -binding site be present outside the EF-hand motif ( Vien et al, 2020 ). Interestingly, we previously found that the EF-hand motif in PKD2L1 is not critical for the Ca 2+ -induced channel activation or the ensuing inactivation in oocytes ( Li et al, 2002 ).…”

Section: Pkd2 As Ca 2+ -Permeable Cation Channelmentioning

confidence: 99%

Role of PKD2 in the endoplasmic reticulum calcium homeostasis

2022

View full text Add to dashboard Cite

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in the PKD1 or PKD2 gene which encodes membrane receptor PKD1 and cation channel PKD2, respectively. PKD2, also called transient receptor potential polycystin-2 (TRPP2), is a Ca2+-permeable channel located on the membrane of cell surface, primary cilia, and endoplasmic reticulum (ER). Ca2+ is closely associated with diverse cellular functions. While ER Ca2+ homeostasis depends on different Ca2+ receptors, channels and transporters, the role of PKD2 within the ER remains controversial. Whether and how PKD2-mediated ER Ca2+ leak relates to ADPKD pathogenesis is not well understood. Here, we reviewed current knowledge about the biophysical and physiological properties of PKD2 and how PKD2 contributes to ER Ca2+ homeostasis.

show abstract

“…These structural studies suggest a role for the cytoplasmic regions in the regulation of PC2 channel activity. However, mutations in the EF‐hand motif resulting in ADPKD have not been reported, and no renal cysts have been observed in a transgenic mouse model with mutations that abrogated the Ca 2+ ‐binding properties of the EF‐hand (Vien, Ng et al., 2020). Moreover, in contrast to the lipid bilayer studies where mutation to the EF‐hand motif prevented PC2 channel activity (Ćelić et al., 2012), there was no loss of channel activity in PC2 patched from the primary cilia with the EF‐hand mutations (Vien, Ng et al., 2020).…”

Section: Introductionmentioning

confidence: 99%

Cardiovascular perspectives of the TRP channel polycystin 2

Márquez-Nogueras

Kuo

2023

The Journal of Physiology

View full text Add to dashboard Cite

Calcium release from the endoplasmic reticulum (ER) is predominantly driven by two key ion channel receptors, inositol 1, 4, 5‐triphosphate receptor (InsP3R) in non‐excitable cells and ryanodine receptor (RyR) in excitable and muscle‐based cells. These calcium transients can be modified by other less‐studied ion channels, including polycystin 2 (PC2), a member of the transient receptor potential (TRP) family. PC2 is found in various cell types and is evolutionarily conserved with paralogues ranging from single‐cell organisms to yeasts and mammals. Interest in the mammalian form of PC2 stems from its disease relevance, as mutations in the PKD2 gene, which encodes PC2, result in autosomal dominant polycystic kidney disease (ADPKD). This disease is characterized by renal and liver cysts, and cardiovascular extrarenal manifestations. However, in contrast to the well‐defined roles of many TRP channels, the role of PC2 remains unknown, as it has different subcellular locations, and the functional understanding of the channel in each location is still unclear. Recent structural and functional studies have shed light on this channel. Moreover, studies on cardiovascular tissues have demonstrated a diverse role of PC2 in these tissues compared to that in the kidney. We highlight recent advances in understanding the role of this channel in the cardiovascular system and discuss the functional relevance of PC2 in non‐renal cells. image

show abstract

Disrupting polycystin-2 EF hand Ca2+ affinity does not alter channel function or contribute to polycystic kidney disease

Cited by 10 publications

References 72 publications

Regenerative Calcium Currents in Renal Primary Cilia

Regenerative Calcium Currents in Renal Primary Cilia

Role of PKD2 in the endoplasmic reticulum calcium homeostasis

Cardiovascular perspectives of the TRP channel polycystin 2

Contact Info

Product

Resources

About