Tyrosine phosphorylation–dependent activation of TRPC6 regulated by PLC-γ1 and nephrin: effect of mutations associated with focal segmental glomerulosclerosis

Kanda, Shoichiro; Harita, Yutaka; Shibagaki, Yoshio; Sekine, Takashi; Igarashi, Takashi; Inoue, Takafumi; Hattori, Satoshi

doi:10.1091/mbc.e10-12-0929

Cited by 58 publications

(56 citation statements)

References 58 publications

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“…Phosphorylation of TRPC channels has been shown to regulate channel activities, membrane trafficking, and formation of protein complexes (36). For example, phosphorylation of Y284 of TRPC6 was shown to be necessary for its trafficking to the plasma membrane (32). Of interest, in addition to the acute effect (Fig.…”

Section: Discussionmentioning

confidence: 99%

Nuclear factor of activated T cells mediates RhoA-induced fibronectin upregulation in glomerular podocytes

Zhu

Aoudjit

et al. 2013

American Journal of Physiology-Renal Physiology

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Glomerulosclerosis is featured by accumulation of the extracellular matrixes in the glomerulus. We showed previously that activation of the small GTPase RhoA in podocytes induces heavy proteinuria and glomerulosclerosis in the mouse. In the current study, we investigated the mechanism by which RhoA stimulates the production of one of the extracellular matrixes, fibronectin, by podocytes, specifically testing the role of nuclear factor of activated T cells (NFAT). Expression of constitutively active RhoA in cultured podocytes activated the fibronectin promoter, upregulated fibronectin protein, and activated NFAT. Expression of constitutively active NFAT in podocytes also activated the fibronectin promoter and upregulated fibronectin protein. RhoA-induced NFAT activation and fibronectin upregulation were both dependent on the calcium/calmodulin pathway and Rho kinase. NFAT activation was also observed in vivo in the rat and mouse models of podocyte injury and proteinuria, and NFAT inhibition ameliorated fibronectin upregulation in the latter. RhoA activation induced a rise of intracellular calcium ion concentration ([Ca2+]i), which was at least in part dependent on the transient receptor potential canonical 6 (TRPC6) cation channel. The results indicate that RhoA activates NFAT by inducing a rise of [Ca2+]i in podocytes, which in turn contributes to fibronectin upregulation. This pathway may be responsible for the pathogenesis of certain glomerular diseases such as hypertension-mediated glomerulosclerosis.

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Section: Discussionmentioning

confidence: 99%

Nuclear factor of activated T cells mediates RhoA-induced fibronectin upregulation in glomerular podocytes

Zhu

Aoudjit

et al. 2013

American Journal of Physiology-Renal Physiology

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“…28 Dent disease is most commonly (60% of cases -type 1) due to an inactivating mutation of the CLCN5 gene, located on Xp11. 22. 29 The vast majority of mutations is either nonsense or missense and severely truncate the protein with complete loss of function.…”

Section: Disorders Of the Proximal Tubulementioning

confidence: 99%

The renal channelopathies

Loudon

Fry

2014

Ann Clin Biochem

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Specific channels permit movement of selected ions through cellular membranes, and are of vital importance in a number of physiological processes, particularly in excitable tissues such as nerve and muscle, but also in endocrine organs and in epithelial biology. Disorders of channel proteins are termed channelopathies, and their importance is increasingly recognised within medicine. In the kidney, ion channels have critical roles enabling sodium and potassium reuptake or excretion along the nephron, in magnesium homeostasis, in the control of water reabsorption in the collecting duct, and in determining glomerular permeability. In this review, we assess the channelopathies encountered in each nephron segment, and see how their molecular and genetic characterisation in the past 20-30 years has furthered our understanding of normal kidney physiology and disease processes, aids correct diagnosis and promises future therapeutic opportunities.

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“…Several stimuli have been shown to activate the channel, including G␣ q -coupled receptors (4,5) and receptor tyrosine kinases (6) as well as direct binding of diacylglycerol (7). In the case of receptor-mediated activation, regulated exocytosis of the channel is at least partially responsible for increasing channel activity (5,6,8). Membrane deformation has also been reported to activate the channel directly (9), although this mechanism remains controversial (10).…”

Section: Gain-of-function Mutations In the Canonical Transient Receptmentioning

confidence: 99%

“…The mutations map to various segments of the protein, predominantly the ankyrin repeats in the amino-terminal cytoplasmic domain and a putative coiled-coil sequence in the carboxyl-terminal cytoplasmic domain. The mechanism(s) whereby these mutations enhance channel activity remains unclear, although there are suggestions that some mutations may alter cell surface localization (12) and binding to nephrin (8). Additional evidence suggests that TRPC6 plays an important role in podocyte function.…”

Section: Gain-of-function Mutations In the Canonical Transient Receptmentioning

confidence: 99%

Gain-of-function Mutations in Transient Receptor Potential C6 (TRPC6) Activate Extracellular Signal-regulated Kinases 1/2 (ERK1/2)

Chiluiza

Krishna

Schumacher

et al. 2013

Journal of Biological Chemistry

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Background: Signaling events affected by disease-associated mutations in TRPC6 are poorly defined. Results: Expression of mutant TRPC6 induces ERK1/2 activation via both cell-autonomous and non-cell-autonomous mechanisms. Conclusion: Mutant TRPC6 activates complex signaling pathways that lead to the release of paracrine factors activating ERK. Significance: Understanding the signaling pathways downstream of gain-of-function TRPC6 is crucial for understanding TRPC6-mediated biology and pathology.

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Tyrosine phosphorylation–dependent activation of TRPC6 regulated by PLC-γ1 and nephrin: effect of mutations associated with focal segmental glomerulosclerosis

Cited by 58 publications

References 58 publications

Nuclear factor of activated T cells mediates RhoA-induced fibronectin upregulation in glomerular podocytes

Nuclear factor of activated T cells mediates RhoA-induced fibronectin upregulation in glomerular podocytes

The renal channelopathies

Gain-of-function Mutations in Transient Receptor Potential C6 (TRPC6) Activate Extracellular Signal-regulated Kinases 1/2 (ERK1/2)

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