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Cilia-enriched oxysterol 7β,27-DHC is required for polycystin ion channel activation
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Cilia-enriched oxysterol 7β,27-DHC is required for polycystin ion channel activation
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Journal Article
Cilia-enriched oxysterol 7β,27-DHC is required for polycystin ion channel activation
2024
Overview
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.
It is currently unknown how environmental cues regulate ciliary Polycystin ion channels on renal epithelial cells. Here authors identify a cilia-enriched oxysterol, 7β,27- dihydroxycholesterol (DHC), as a necessary activator of the polycystin complex
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 631/45
/ 9/74
/ 9/97
/ Animals
/ Binding
/ Cilia
/ Humanities and Social Sciences
/ Humans
/ INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
/ Mice
/ Mutation
/ Nephrons
/ Polycystic kidney disease 1 protein
/ Polycystic Kidney, Autosomal Dominant - genetics
/ Polycystic Kidney, Autosomal Dominant - metabolism
/ Polycystic Kidney, Autosomal Dominant - pathology
/ Science
