Specific TRPC6 Channel Activation, a Novel Approach to Stimulate Keratinocyte Differentiation

Müller, Margarethe; Essin, Kirill; Hill, Kerstin; Beschmann, Heike A.; Rubant, Simone; Schempp, Christoph M.; Gollasch, Maik; Boehncke, Wolf‐Henning; Harteneck, Christian; Müller, Walter E.; Leuner, Kristina

doi:10.1074/jbc.m801844200

Cited by 101 publications

(86 citation statements)

References 37 publications

(53 reference statements)

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“…In psoriatic skin lesions, the expression of TRPC6 is markedly reduced (Leuner et al, 2011). Activation of TRPC5 by hyperforin partially restores the disturbed keratinocyte differentiation in psoriatic lesions (Müller et al, 2008). This implies a therapeutic potential for TRPC6 agonist creams in the pharmacotherapy of psoriasis.…”

Section: Dietary Mgmentioning

confidence: 92%

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

2014

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Section: Dietary Mgmentioning

confidence: 92%

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

2014

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“…Usually, the stimulation effects were observed at low doses of plant preparations with inhibitory effects at higher ones [47,48]. For example, it has been reported that hyperforin from H. perforatum can induce keratinocyte differentiation in vitro [49]. Stimulation of proliferation was found to be beneficial for normal cells or tissues which require rejuvenation and regeneration and it is undesirable for cancer cells due to promoting cancer malignization [48,50].…”

Section: Plant Extracts Protect Yeast Cells Against H 2 O 2 At Acidicmentioning

confidence: 99%

Effects of pH on antioxidant and prooxidant properties of common medicinal herbs

2016

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Background: We studied in vitro and vivo antioxidant and prooxidant abilities of aqueous extracts from Rosa canina L., Rhodiola rosea L., Hypericum perforatum L., and Gentiana lutea L. Methodology: Total antioxidant capacity was measured by four assays (phosphomolybdate method, Fe3+-reducing activity, ABTS•+ scavenging, H2O2 scavenging). Prooxidant activity was estimated by H2O2 production. Yeast viability in the presence of H2O2 and/or plant extracts was determined by plating or by counting live cells’ number. Results: Plant extracts differed in the total phenolic content (R. canina > R. rosea > H. perforatum > G. lutea) which clearly correlated with their ABTS•+ scavenging activity (R2 = 0.963). H2O2 scavenging activity was not clearly associated with plant phenol levels and was significantly higher in acidic, than in alkaline medium. In line with this, plant extracts effectively protected yeast S. cereviasiae against H2O2 and stimulated reproductive ability of yeast cells at acidic but not at alkaline pH. At alkaline pH, plant extracts produced certain amounts of H2O2 which were related to their phenolic content. Conclusion: The antioxidant activity of plant extracts is decreased at alkaline pH with an increase in the prooxidant activity. It reduces protective capacity of plant extracts against oxidative and other stresses in vivo.

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“…As a nonselective cation channel, TRPC6 is permeable for sodium and for calcium. Thus, it triggers calcium-dependent intracellular signaling processes necessary for cell differentiation (Leuner et al, 2007;Mü ller et al, 2008). In PC12 cells, hyperforin mimics NGF-induced cellular responses involved in neurite outgrowth (Leuner et al, 2007).…”

mentioning

confidence: 99%

Simple 2,4-Diacylphloroglucinols as Classic Transient Receptor Potential-6 Activators—Identification of a Novel Pharmacophore

Leuner

Heiser²,

Derksen³

et al. 2009

Mol Pharmacol

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The naturally occurring acylated phloroglucinol derivative hyperforin was recently identified as the first specific canonical transient receptor potential-6 (TRPC6) activator. Hyperforin is the major antidepressant component of St. John's wort, which mediates its antidepressant-like properties via TRPC6 channel activation. However, its pharmacophore moiety for activating TRPC6 channels is unknown. We hypothesized that the phloroglucinol moiety could be the essential pharmacophore of hyperforin and that its activity profile could be due to structural similarities with diacylglycerol (DAG), an endogenous nonselective activator of TRPC3, TRPC6, and TRPC7. Accordingly, a few 2-acyl and 2,4-diacylphloroglucinols were tested for their hyperforin-like activity profiles. We used a battery of experimental models to investigate all functional aspects of TRPC6 activation, including ion channel recordings, Ca 2ϩ imaging, neurite outgrowth, and inhibition of synaptosomal uptake. Phloroglucinol itself was inactive in all of our assays, which was also the case for 2-acylphloroglucinols. For TRPC6 activation, the presence of two symmetrically acyl-substitutions with appropriate alkyl chains in the phloroglucinol moiety seems to be an essential prerequisite. Potencies of these compounds in all assays were comparable with that of hyperforin for activating the TRPC6 channel. Finally, using structure-based modeling techniques, we suggest a binding mode for hyperforin to TRPC6. Based on this modeling approach, we propose that DAG is able to activate TRPC3, TRPC6, and TRPC7 because of higher flexibility within the chemical structure of DAG compared with the rather rigid structures of hyperforin and the 2,4-diacylphloroglucinol derivatives.

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Specific TRPC6 Channel Activation, a Novel Approach to Stimulate Keratinocyte Differentiation

Cited by 101 publications

References 37 publications

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

Effects of pH on antioxidant and prooxidant properties of common medicinal herbs

Simple 2,4-Diacylphloroglucinols as Classic Transient Receptor Potential-6 Activators—Identification of a Novel Pharmacophore

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