ArticleThe Journal of biological chemistry2013
Gain-of-function mutations in transient receptor potential C6 (TRPC6) activate extracellular signal-regulated kinases 1/2 (ERK1/2).
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 59 citations in OpenAlex.
- Targeting the epidermal growth factor receptor (EGFR/ErbB) for the potential treatment of renal pathologies.Frontiers in pharmacology · 2024Review
- Store-operated CaExperimental biology and medicine (Maywood, N.J.) · 2023Review
- Ion channels and channelopathies in glomeruli.Physiological reviews · 2023Review
- Pharmacological TRPC6 inhibition improves survival and muscle function in mice with Duchenne muscular dystrophy.JCI insight · 2022Article
- Article
- Trpc6 gain-of-function disease mutation enhances phosphatidylserine exposure in murine platelets.PloS one · 2022Article
- The glomerular filtration barrier: a structural target for novel kidney therapies.Nature reviews. Drug discovery · 2021Review
- The Zebrafish Model to Understand Epigenetics in Renal Diseases.International journal of molecular sciences · 2021Review
- Review
- Stretch-Induced Biased Signaling in Angiotensin II Type 1 and Apelin Receptors for the Mediation of Cardiac Contractility and Hypertrophy.Frontiers in physiology · 2020Review
- Article
- TRPC6 Binds to and Activates Calpain, Independent of Its Channel Activity, and Regulates Podocyte Cytoskeleton, Cell Adhesion, and Motility.Journal of the American Society of Nephrology : JASN · 2019Article
- Contribution of Coiled-Coil Assembly to CaJournal of the American Society of Nephrology : JASN · 2019Article
- Transmembrane insertases andThe Journal of biological chemistry · 2019Article
- Role of TRPC6 in Progression of Diabetic Kidney Disease.Current hypertension reports · 2019Review
- Epidermal growth factor receptor controls glycogen phosphorylase in T cells through small GTPases of the RAS family.The Journal of biological chemistry · 2019Article
- Analysis of 24 genes reveals a monogenic cause in 11.1% of cases with steroid-resistant nephrotic syndrome at a single center.Pediatric nephrology (Berlin, Germany) · 2018Article
- Integration of TRPC6 and NADPH oxidase activation in lysophosphatidylcholine-induced TRPC5 externalization.American journal of physiology. Cell physiology · 2017Article
- Klotho suppresses the renin-angiotensin system in adriamycin nephropathy.Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association · 2017Article
- Deletion of diacylglycerol-responsive TRPC genes attenuates diabetic nephropathy by inhibiting activation of the TGFβ1 signaling pathway.American journal of translational research · 2017Article
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Gain-of-function mutations in the canonical transient receptor potential 6 (TRPC6) gene are a cause of autosomal dominant focal segmental glomerulosclerosis (FSGS). The mechanisms whereby abnormal TRPC6 activity results in proteinuria remain unknown. The ERK1/2 MAPKs are activated in glomeruli and podocytes in several proteinuric disease models. We therefore examined whether FSGS-associated mutations in TRPC6 result in activation of these kinases. In 293T cells and cultured podocytes, overexpression of gain-of-function TRPC6 mutants resulted in increased ERK1/2 phosphorylation, an effect dependent upon channel function. Pharmacologic inhibitor studies implicated several signaling mediators, including calmodulin and calcineurin, supporting the importance of TRPC6-mediated calcium influx in this process. Through medium transfer experiments, we uncovered two distinct mechanisms for ERK activation by mutant TRPC6, a cell-autonomous, EGF receptor-independent mechanism and a non-cell-autonomous mechanism involving metalloprotease-mediated release of a presumed EGF receptor ligand. The inhibitors KN-92 and H89 were able to block both pathways in mutant TRPC6 expressing cells as well as the prolonged elevation of intracellular calcium levels upon carbachol stimulation seen in these cells. However, these effects appear to be independent of their effects on calcium/calmodulin-dependent protein kinase II and PKA, respectively. Phosphorylation of Thr-70, Ser-282, and Tyr-31/285 were not necessary for ERK activation by mutant TRPC6, although a phosphomimetic TRPC6 S282E mutant was capable of ERK activation. Taken together, these results identify two pathways downstream of mutant TRPC6 leading to ERK activation that may play a role in the development of FSGS.
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