Journal article
Soluble klotho regulates TRPC6 calcium signaling via lipid rafts, independent of the FGFR-FGF23 pathway
The FASEB journal, Vol.33(8), pp.9182-9193
05/07/2019
DOI: 10.1096/fj.201900321R
PMCID: PMC6662984
PMID: 31063704
Abstract
Soluble klotho (sKlotho), the shed ectodomain of α-klotho, protects the heart by down-regulating transient receptor potential canonical isoform 6 (TRPC6)–mediated calcium signaling. Binding to α2-3-sialyllactose moiety of gangliosides in lipid rafts and inhibition of raft-dependent signaling underlies the mechanism. A recent 3-Å X-ray structure of sKlotho in complex with fibroblast growth factor receptor (FGFR) and fibroblast growth factor 23 (FGF23) indicates that its β6α6 loop might block access to the proposed binding site for α2-3-sialyllactose. It was concluded that sKlotho only functions in complex with FGFR and FGF23 and that sKlotho’s pleiotropic effects all depend on FGF23. Here, we report that sKlotho can inhibit TRPC6 channels expressed in cells lacking endogenous FGFRs. Structural modeling and molecular docking show that a repositioned β6α6 loop allows sKlotho to bind α2-3-sialyllactose. Molecular dynamic simulations further show the α2-3-sialyllactose–bound sKlotho complex to be stable. Domains mimicking sKlotho’s sialic acid–recognizing activity inhibit TRPC6. The results strongly support the hypothesis that sKlotho can exert effects independent of FGF23 and FGFR.—Wright, J. D., An, S.-W., Xie, J., Lim, C., Huang, C.-L. Soluble klotho regulates TRPC6 calcium signaling
via
lipid rafts, independent of the FGFR-FGF23 pathway.
Details
- Title: Subtitle
- Soluble klotho regulates TRPC6 calcium signaling via lipid rafts, independent of the FGFR-FGF23 pathway
- Creators
- Jon D. Wright - Institute of Biomedical Sciences, Academia SinicaSung-Wan An - Roy J. and Lucille A. Carver College of MedicineJian Xie - Roy J. and Lucille A. Carver College of MedicineCarmay Lim - National Tsing Hua UniversityChou-Long Huang - Roy J. and Lucille A. Carver College of Medicine
- Resource Type
- Journal article
- Publication Details
- The FASEB journal, Vol.33(8), pp.9182-9193
- Publisher
- Federation of American Societies for Experimental Biology
- DOI
- 10.1096/fj.201900321R
- PMID
- 31063704
- PMCID
- PMC6662984
- ISSN
- 0892-6638
- eISSN
- 1530-6860
- Grant note
- DOI: 10.13039/100000002, name: National Institutes of Health; DOI: 10.13039/100000062, name: National Institute of Diabetes and Digestive and Kidney Diseases, award: DK100605, DK109887; DOI: 10.13039/100007225, name: Ministry of Science and Technology, award: 106‐14; DOI: 10.13039/501100001869, name: Academia Sinica
- Language
- English
- Date published
- 05/07/2019
- Academic Unit
- Nephrology; Internal Medicine
- Record Identifier
- 9984360148602771
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