Cilia-enriched oxysterol 7β,27-DHC is required for polycystin ion channel activation

Kodaji Ha, Nadine Mundt-Machado, Paola Bisignano, Aide Pinedo, David R. Raleigh, Gabriel Loeb, Jeremy F. Reiter, Erhu Cao and Markus Delling ()
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Kodaji Ha: University of California San Francisco
Nadine Mundt-Machado: University of California San Francisco
Paola Bisignano: Vanderbilt University
Aide Pinedo: University of California San Francisco
David R. Raleigh: San Francisco
Gabriel Loeb: University of California
Jeremy F. Reiter: San Francisco
Erhu Cao: University of Utah School of Medicine
Markus Delling: University of California San Francisco

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50318-9

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