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Abstract: FR-OR005

Molecular Regulation of Polycystin TRP Channels

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic

Author

  • DeCaen, Paul G., Northwestern University, Chicago, Illinois, United States
Background

Autosomal dominant polycystic kidney disease (ADPKD) causes progressive renal failure and can be caused by variants in the PKD2 genes which encode the polycystin-2 transient receptor ion channel (TRP). Despite our strong understanding of the genetic basis of ADPKD, we still do not know how polycystin-2 ion channel function is molecularly regulated. This basic question remains outstanding because polycystin-2 localizes to the primary cilium—an antenna-like organelle that requires innovative tools to study. Recently, our lab achieved the first heterologous and native electrophysiological characterization of TRPP2 in the primary cilia membrane. With our collaborators, we also published the first high-resolution structure of polycystin-2, which has provided a molecular context for understanding ADPKD variants and clues to its structural regulation.

Methods

We have developed novel methodologies which include: cilia electrophysiology, cilia-specific calcium sensors, super-resolution imaging, cryo-EM structural determination and ADPKD animal models to assay polycystin activity directly from the primary cilia membrane. We have deployed these state-of-the-art methods to provide the most accurate description of the biophysical regulation of polycystin-2 and the related polycystin-like (encoded by PKD2L1) channels, providing results in real-time and atomic resolution.

Results

We have interrogated multiple mutations within three structural domains within polycystin-2 and assessed their impact on the opening and closing of the ion conductive pore, the oligomictic stability of the tetrameric channel and their trafficking to the primary cilia membrane.

Conclusion

Our results provide a biophysical framework for understanding of polycystin-2’s molecular regulation. We have determined that polycystin-2 integrates polymodal stimuli to control the channels voltage dependent gating. Domains within the channel independently respond to stimuli (e.g. intra-ciliary calcium), but the final open step is ultimately controlled by four-helix bundle which senses membrane potential. Based on these structural observations, we propose mechanistic hypotheses regarding the impact variants found within these domains.

Funding

  • NIDDK Support