76 research outputs found
Genomic Analysis to Avoid Misdiagnosis of Adults With Bilateral Renal Cysts
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TRPP2 and TRPV4 form a polymodal sensory channel complex
No full textThe primary cilium has evolved as a multifunctional cellular compartment that decorates most vertebrate cells. Cilia sense mechanical stimuli in various organs, but the molecular mechanisms that convert the deflection of cilia into intracellular calcium transients have remained elusive. Polycystin-2 (TRPP2), an ion channel mutated in polycystic kidney disease, is required for ciliamediated calcium transients but lacks mechanosensitive properties. We find here that TRPP2 utilizes TRPV4 to form a mechano- and thermosensitive molecular sensor in the cilium. Depletion of TRPV4 in renal epithelial cells abolishes flow-induced calcium transients, demonstrating that TRPV4, like TRPP2, is an essential component of the ciliary mechanosensor. Because TRPV4-deficient zebrafish and mice lack renal cysts, our findings challenge the concept that defective ciliary flow sensing constitutes the fundamental mechanism of cystogenesis.sponsorship: We are grateful to N. Katsanis for sharing unpublished information and V. Flockerzi, S. Heller, and W. Liedtke for plasmids and antibodies. We thank M. Caterina for discussions and support with the TRPV4 knockout animals, and Emily Kim for helpful suggestions. This work was supported by the Deutsche Forschungsgemeinschaft (support given to G. Walz), a PKD Foundation Fellowship (to M. Kottgen), the National Kidney Foundation of Maryland, Inc. (grant GM073704 to T. Watnick), the Human Frontiers Science Program (grant RGP 32/2004 to B. Nilius) and Excellentie financiering (grant EF/95/010 to B. Nilius), and the National Institutes of Health (grants DK48006 and DK51259 to G. G. Germino). (Deutsche Forschungsgemeinschaft, PKD Foundation, National Kidney Foundation of Maryland, Inc|GM073704, Human Frontiers Science Program|RGP 32/2004, Excellentie financiering|EF/95/010, National Institutes of Health|DK48006, National Institutes of Health|DK51259)status: Publishe
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