ArticleProceedings of the National Academy of Sciences of the United States of America2016
Function and regulation of TRPP2 ion channel revealed by a gain-of-function mutant.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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Who cites it
48 citing papers in PubMed, 73 citations in OpenAlex.
- Structural basis of lipid-dependent allosteric gating mechanisms for PC1-PC2 ion channel.Nature communications · 2026Article
- Regulation of the PKD2 channel function and associated disease phenotypes by RASSF4.Communications biology · 2026Article
- Actually, what is a gain-of-function mutation?Genetics · 2026Article
- A Ciliary Phosphoinositide Pathway Regulates the Dosage of Polycystins in Primary Cilia.Journal of the American Society of Nephrology : JASN · 2026Article
- Physiological functions and pharmacological targeting of transient receptor potential channels.Pharmacological reviews · 2025Review
- Cleavage of N-terminus of polycystin-1 increases calcium permeability of polycystin-1/2 receptor channel complexes.JCI insight · 2025Article
- Physiologic mechanisms underlying polycystic kidney disease.Physiological reviews · 2025Review
- Metabolic Reprogramming in Autosomal Dominant Polycystic Kidney Disease: Role in Cystogenesis and Novel Therapeutic Approaches.Biomedicines · 2025Review
- Pathogenic variants in the polycystin pore helix cause distinct forms of channel dysfunction.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Ion channel function of polycystin-2/polycystin-1 heteromer revealed by structure-guided mutagenesis.FEBS letters · 2025Article
- Identification of polycystin 2 missense mutants targeted for endoplasmic reticulum-associated degradation.American journal of physiology. Cell physiology · 2025Article
- Disease-associated missense mutations in the pore loop of polycystin-2 alter its ion channel function in a heterologous expression system.The Journal of biological chemistry · 2024Article
- Calcium signalling and transport in the kidney.Nature reviews. Nephrology · 2024Review
- Cilia-enriched oxysterol 7β,27-DHC is required for polycystin ion channel activation.Nature communications · 2024Article
- Vascular polycystin proteins in health and disease.Microcirculation (New York, N.Y. : 1994) · 2024Review
- Molecular and structural basis of the dual regulation of the polycystin-2 ion channel by small-molecule ligands.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Leucine-Rich Repeat in Polycystin-1 Suppresses Cystogenesis in a Zebrafish (International journal of molecular sciences · 2024Article
- Article
- Calcium Homeostasis, Transporters, and Blockers in Health and Diseases of the Cardiovascular System.International journal of molecular sciences · 2023Review
- A plasma membrane-localized polycystin-1/polycystin-2 complex in endothelial cells elicits vasodilation.eLife · 2022Article
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Authors and funding
13 authors at 4 institutions in 1 country.
Funding
Abstract
Mutations in polycystin-1 and transient receptor potential polycystin 2 (TRPP2) account for almost all clinically identified cases of autosomal dominant polycystic kidney disease (ADPKD), one of the most common human genetic diseases. TRPP2 functions as a cation channel in its homomeric complex and in the TRPP2/polycystin-1 receptor/ion channel complex. The activation mechanism of TRPP2 is unknown, which significantly limits the study of its function and regulation. Here, we generated a constitutively active gain-of-function (GOF) mutant of TRPP2 by applying a mutagenesis scan on the S4-S5 linker and the S5 transmembrane domain, and studied functional properties of the GOF TRPP2 channel. We found that extracellular divalent ions, including Ca(2+), inhibit the permeation of monovalent ions by directly blocking the TRPP2 channel pore. We also found that D643, a negatively charged amino acid in the pore, is crucial for channel permeability. By introducing single-point ADPKD pathogenic mutations into the GOF TRPP2, we showed that different mutations could have completely different effects on channel activity. The in vivo function of the GOF TRPP2 was investigated in zebrafish embryos. The results indicate that, compared with wild type (WT), GOF TRPP2 more efficiently rescued morphological abnormalities, including curly tail and cyst formation in the pronephric kidney, caused by down-regulation of endogenous TRPP2 expression. Thus, we established a GOF TRPP2 channel that can serve as a powerful tool for studying the function and regulation of TRPP2. The GOF channel may also have potential application for developing new therapeutic strategies for ADPKD.
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