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Published on: March 28, 2025
The native TRPP2-dependent channel of murine renal primary cilia
Steven J Kleene1, Nancy K Kleene2
1Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio steve@syrano.acb.uc.edu.
Insights
Autosomal dominant polycystic kidney disease (ADPKD) is linked to mutations in polycystin-1 (PC1) and polycystin-2 (TRPP2). This study identifies a TRPP2-dependent cation channel in the renal primary cilium, crucial for understanding ADPKD.
Area of Science:
- Nephrology
- Molecular Biology
- Biophysics
Background:
- Autosomal dominant polycystic kidney disease (ADPKD) is a prevalent, life-threatening monogenic kidney disorder.
- Mutations in polycystin-1 (PC1) or polycystin-2 (TRPP2) cause ADPKD, with both proteins localized to the renal primary cilium.
- The primary cilium is implicated in renal cystogenesis, and PC1/TRPP2 are thought to counteract this process.
Purpose of the Study:
- To investigate the electrophysiological properties of TRPP2 in the native ciliary membrane.
- To characterize the function of TRPP2 in renal epithelial cells.
Main Methods:
- Direct electrophysiological recordings from the cilia of mIMCD-3 cells (murine renal epithelial cell line).
- Utilized CRISPR/Cas9 genome editing to knock out TRPP2.
- Analyzed cation permeability and single-channel conductance.
Main Results:
- A large-conductance cation channel, impermeable to chloride, was observed in approximately one-third of examined cilia.
- The channel exhibited cation permeability (PK:PCa:PNa = 1:0.55:0.14) and significant single-channel conductance.
- Channel activity was sensitive to membrane depolarization and micromolar cytoplasmic Ca2+, with increased open probability.
- TRPP2 knockout abolished the observed channel current, confirming its TRPP2 dependence.
Conclusions:
- Identified and characterized a TRPP2-dependent cation channel in the renal primary cilium.
- This channel's properties suggest a role in regulating ion transport within the cilium.
- Findings provide insights into the molecular mechanisms underlying ADPKD and potential therapeutic targets.
Abstract:
Autosomal dominant polycystic kidney disease (ADPKD) is the most common life-threatening monogenic renal disease. ADPKD results from mutations in either of two proteins: polycystin-1 (also known as PC1 or PKD1) or transient receptor potential cation channel, subfamily P, member 2 (TRPP2, also known as polycystin-2, PC2, or PKD2). Each of these proteins is expressed in the primary cilium that extends from many renal epithelial cells. Existing evidence suggests that the cilium can promote renal cystogenesis, while PC1 and TRPP2 counter this cystogenic effect. To better understand the function of TRPP2, we investigated its electrophysiological properties in the native ciliary membrane. We recorded directly from the cilia of mIMCD-3 cells, a murine cell line of renal epithelial origin. In one-third of cilia examined, a large-conductance channel was observed. The channel was not permeable to Cl¯ but conducted cations with permeability ratios PK:PCa:PNa of 1:0.55:0.14. The single-channel conductance ranged from 97 pS in typical physiological solutions to 189 pS in symmetrical 145 mM KCl. Open probability of the channel was very sensitive to membrane depolarization or increasing cytoplasmic free Ca2+ in the low micromolar range, with the open probability increasing in either case. Knocking out TRPP2 by CRISPR/Cas9 genome editing eliminated the channel current, establishing it as TRPP2 dependent. Possible mechanisms for activating the TRPP2-dependent channel in the renal primary cilium are discussed.
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