PI3-kinase promotes TRPV2 activity independently of channel translocation to the plasma membrane |
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Authors: | Penna Aubin Juvin Véronique Chemin Jean Compan Vincent Monet Michael Rassendren François-A |
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Affiliation: | Department of Pharmacology, Institut de Génomique Fonctionnelle, CNRS UMR 5203, INSERM U661, Université Montpellier I, Université Montpellier II, 141 rue de la Cardonille, 34396 Montpellier Cedex, France. |
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Abstract: | Cellular or chemical activators for most transient receptor potential channels of the vanilloid subfamily (TRPV) have been identified in recent years. A remarkable exception to this is TRPV2, for which cellular events leading to channel activation are still a matter of debate. Diverse stimuli such as extreme heat or phosphatidylinositol-3 kinase (PI3-kinase) regulated membrane insertion have been shown to promote TRPV2 channel activity. However, some of these results have proved difficult to reproduce and may underlie different gating mechanisms depending on the cell type in which TRPV2 channels are expressed. Here, we show that expression of recombinant TRPV2 can induce cytotoxicity that is directly related to channel activity since it can be prevented by introducing a charge substitution in the pore-forming domain of the channel, or by reducing extracellular calcium. In stably transfected cells, TRPV2 expression results in an outwardly rectifying current that can be recorded at all potentials, and in an increase of resting intracellular calcium concentration that can be partly prevented by serum starvation. Using cytotoxicity as a read-out of channel activity and direct measurements of cell surface expression of TRPV2, we show that inhibition of the PI3-kinase decreases TRPV2 channel activity but does not affect the trafficking of the channel to the plasma membrane. It is concluded that PI3-kinase induces or modulates the activity of recombinant TRPV2 channels; in contrast to the previously proposed mechanism, activation of TRPV2 channels by PI3-kinase is not due to channel translocation to the plasma membrane. |
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Keywords: | PI3-kinase TRPV2 Cytotoxicity Translocation |
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