| Structural highlights
Disease
[TRPC6_HUMAN] Familial idiopathic steroid-resistant nephrotic syndrome with focal segmental hyalinosis. The disease is caused by mutations affecting the gene represented in this entry.
Function
[TRPC6_HUMAN] Thought to form a receptor-activated non-selective calcium permeant cation channel (PubMed:19936226, PubMed:23291369). Probably is operated by a phosphatidylinositol second messenger system activated by receptor tyrosine kinases or G-protein coupled receptors. Activated by diacylglycerol (DAG) in a membrane-delimited fashion, independently of protein kinase C (PubMed:26892346). Seems not to be activated by intracellular calcium store depletion.[1] [2] [3]
Publication Abstract from PubMed
Transient receptor potential canonical (TRPC) proteins form nonselective cation channels that play physiological roles in a wide variety of cells. Despite growing evidence supporting the therapeutic potential of TRPC6 inhibition in treating pathological cardiac and renal conditions, mechanistic understanding of TRPC6 function and modulation remains obscure. Here we report cryo-EM structures of TRPC6 in both antagonist-bound and agonist-bound states. The structures reveal two novel recognition sites for the small-molecule modulators corroborated by mutagenesis data. The antagonist binds to a cytoplasm-facing pocket formed by S1-S4 and the TRP helix, whereas the agonist wedges at the subunit interface between S6 and the pore helix. Conformational changes upon ligand binding illuminate a mechanistic rationale for understanding TRPC6 modulation. Furthermore, structural and mutagenesis analyses suggest several disease-related mutations enhance channel activity by disrupting interfacial interactions. Our results provide principles of drug action that may facilitate future design of small molecules to ameliorate TRPC6-mediated diseases.
Structural basis for pharmacological modulation of the TRPC6 channel.,Bai Y, Yu X, Chen H, Horne D, White R, Wu X, Lee P, Gu Y, Ghimire-Rijal S, Lin DC, Huang X Elife. 2020 Mar 9;9. pii: 53311. doi: 10.7554/eLife.53311. PMID:32149605[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Heeringa SF, Moller CC, Du J, Yue L, Hinkes B, Chernin G, Vlangos CN, Hoyer PF, Reiser J, Hildebrandt F. A novel TRPC6 mutation that causes childhood FSGS. PLoS One. 2009 Nov 10;4(11):e7771. doi: 10.1371/journal.pone.0007771. PMID:19936226 doi:http://dx.doi.org/10.1371/journal.pone.0007771
- ↑ Hofstra JM, Lainez S, van Kuijk WH, Schoots J, Baltissen MP, Hoefsloot LH, Knoers NV, Berden JH, Bindels RJ, van der Vlag J, Hoenderop JG, Wetzels JF, Nijenhuis T. New TRPC6 gain-of-function mutation in a non-consanguineous Dutch family with late-onset focal segmental glomerulosclerosis. Nephrol Dial Transplant. 2013 Jul;28(7):1830-8. doi: 10.1093/ndt/gfs572. Epub, 2013 Jan 4. PMID:23291369 doi:http://dx.doi.org/10.1093/ndt/gfs572
- ↑ Riehle M, Buscher AK, Gohlke BO, Kassmann M, Kolatsi-Joannou M, Brasen JH, Nagel M, Becker JU, Winyard P, Hoyer PF, Preissner R, Krautwurst D, Gollasch M, Weber S, Harteneck C. TRPC6 G757D Loss-of-Function Mutation Associates with FSGS. J Am Soc Nephrol. 2016 Sep;27(9):2771-83. doi: 10.1681/ASN.2015030318. Epub 2016 , Feb 18. PMID:26892346 doi:http://dx.doi.org/10.1681/ASN.2015030318
- ↑ Bai Y, Yu X, Chen H, Horne D, White R, Wu X, Lee P, Gu Y, Ghimire-Rijal S, Lin DC, Huang X. Structural basis for pharmacological modulation of the TRPC6 channel. Elife. 2020 Mar 9;9. pii: 53311. doi: 10.7554/eLife.53311. PMID:32149605 doi:http://dx.doi.org/10.7554/eLife.53311
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