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University of California, San Francisco, 현 University of Pittsburgh

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Nat. Commun., Jul 31 2024, 15 (1) 6468 | https://doi.org/10.1038/s41467-024-50318-9 Cilia-enriched oxysterol 7β,27-DHC is required for polycystin ion channel activation

Kodaji Ha¹, Nadine Mundt-Machado¹, Paola Bisignano², Aide Pinedo¹, David R. Raleigh³, Gabriel Loeb⁴, Jeremy F. Reiter^5,6, Erhu Cao⁷ & Markus Delling¹

¹Department of Physiology, University of California San Francisco, San Francisco, CA, USA.
²Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.
³Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, USA.
⁴Department of Medicine, University of California, San Francisco, CA, USA.
⁵Department of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA.
⁶Chan Zuckerberg Biohub, San Francisco, CA, USA.
⁷Department of Biochemistry, Universityof Utah School of Medicine, Salt Lake City, UT, USA.

Corresponding author
Correspondence to Markus Delling.

Abstract

Polycystin-1 (PC-1) and PC-2 form a heteromeric ion channel complex that is abundantly expressed in primary cilia of renal epithelial cells. This complex functions as a non-selective cation channel, and mutations within the polycystin complex cause autosomal dominant polycystic kidney disease (ADPKD). The spatial and temporal regulation of the polycystin complex within the ciliary membrane remains poorly understood. Using both whole-cell and ciliary patch-clamp recordings, we identify a cilia-enriched oxysterol, 7β,27-dihydroxycholesterol (DHC), that serves as a necessary activator of the polycystin complex. We further identify an oxysterol-binding pocket within PC-2 and showed that mutations within this binding pocket disrupt 7β,27-DHC-dependent polycystin activation. Pharmacologic and genetic inhibition of oxysterol synthesis reduces channel activity in primary cilia. In summary, our findings reveal a regulator of the polycystin complex. This oxysterol-binding pocket in PC-2 may provide a specific target for potential ADPKD therapeutics.

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