Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Graziani, A; Poteser, M; Heupel, WM; Schleifer, H; Krenn, M; Drenckhahn, D; Romanin, C; Baumgartner, W; Groschner, K.
Cell-cell contact formation governs Ca2+ signaling by TRPC4 in the vascular endothelium: evidence for a regulatory TRPC4-beta-catenin interaction.
J Biol Chem. 2010; 285(6):4213-4223
Doi: 10.1074/jbc.M109.060301
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- Führende Autor*innen der Med Uni Graz
- Groschner Klaus
- Co-Autor*innen der Med Uni Graz
- Poteser Michael
- Schleifer Hannes
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- Abstract:
- TRPC4 is well recognized as a prominent cation channel in the vascular endothelium, but its contribution to agonist-induced endothelial Ca(2+) entry is still a matter of controversy. Here we report that the cellular targeting and Ca(2+) signaling function of TRPC4 is determined by the state of cell-cell adhesions during endothelial phenotype transitions. TRPC4 surface expression in human microvascular endothelial cells (HMEC-1) increased with the formation of cell-cell contacts. Epidermal growth factor recruited TRPC4 into the plasma membrane of proliferating cells but initiated retrieval of TRPC4 from the plasma membrane in quiescent, barrier-forming cells. Epidermal growth factor-induced Ca(2+) entry was strongly promoted by the formation of cell-cell contacts, and both siRNA and dominant negative knockdown experiments revealed that TRPC4 mediates stimulated Ca(2+) entry exclusively in proliferating clusters that form immature cell-cell contacts. TRPC4 co-precipitated with the junctional proteins beta-catenin and VE-cadherin. Analysis of cellular localization of fluorescent fusion proteins provided further evidence for recruitment of TRPC4 into junctional complexes. Analysis of TRPC4 function in the HEK293 expression system identified beta-catenin as a signaling molecule that enables cell-cell contact-dependent promotion of TRPC4 function. Our results place TRPC4 as a Ca(2+) entry channel that is regulated by cell-cell contact formation and interaction with beta-catenin. TRPC4 is suggested to serve stimulated Ca(2+) entry in a specific endothelial state during the transition from a proliferating to a quiescent phenotype. Thus, TRPC4 may adopt divergent, as yet unappreciated functions in endothelial Ca(2+) homeostasis and emerges as a potential key player in endothelial phenotype switching and tuning of cellular growth factor signaling.
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- Antigens, CD - metabolism
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- Cadherins - metabolism
- Calcium - metabolism
- Cell Adhesion - drug effects
- Cell Communication - physiology
- Cell Line -
- Cell Membrane - drug effects Cell Membrane - metabolism
- Cell Proliferation - drug effects
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- Epidermal Growth Factor - pharmacology
- Fluorescence Resonance Energy Transfer -
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- Immunoprecipitation -
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- TRPC Cation Channels - genetics TRPC Cation Channels - metabolism
- beta Catenin - metabolism