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Rapid vesicular translocation and insertion of TRP channels

Abstract

The broadly expressed transient receptor potential (TRP) family of ion channels are permeant to cations, most resulting in increased intracellular calcium. However, their regulation and gating is not well understood. Here, we report that growth factor stimulation initiates the rapid translocation of the transient receptor potential ion channel, TRPC5, from vesicles held in reserve just under the plasma membrane. This process, which we term 'rapid vesicular insertion of TRP' (RiVIT), dramatically increases membrane-associated TRPC5 channels and functional TRPC5 current, resulting in tight spatial–temporal control of these Ca2+-permeant nonselective channels. Epidermal growth factor (EGF)-induced incorporation of functional TRP channels requires phosphatidylinositide 3-kinase (PI(3)K), the Rho GTPase Rac1 and phosphatidylinositol 4-phosphate 5-kinase (PIP(5)Kα). The increase in TRPC5 availability affects neurite extension rates in cultured hippocampal neurons, and may be a general mechanism for initiating Ca2+ influx and cell morphological changes in response to stimuli.

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Figure 1: EGF stimulation rapidly induces TRPC5 channel translocation to the plasma membrane.
Figure 2: Functional TRPC5 channels are accessible to the surface.
Figure 3: Insertion of TRPC5 channels into the plasma membrane is PI(3)K and Rac1 dependent.
Figure 4: Rac1 is sufficient to stimulate TRPC5 translocation.
Figure 5: TRPC5 membrane insertion is dependent on activation of PIP(5)Kα.
Figure 6: Growth factors induce rapid TRPC5 surface accessibility in primary hippocampal neurons.
Figure 7: TRPC5 surface expression affects hippocampal neurite outgrowth rates.
Figure 8: Schematic diagram of rapid vesicular insertion of TRP (RiVIT).

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Acknowledgements

We thank M. Greenberg for reagents, and L. Cantley, D. van Vactor, T. Swartz, D. Corey, P. Greer, K. Tolias and members of the Clapham laboratory for valuable discussion, especially E. Oancea. This work was supported by the Harvard Biophysics Training Grant (V.B.), a Howard Hughes Medical Institute Predoctoral Fellowship (A.G.) and the Howard Hughes Medical Institute (D.E.C).

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Correspondence to David E. Clapham.

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Bezzerides, V., Ramsey, I., Kotecha, S. et al. Rapid vesicular translocation and insertion of TRP channels. Nat Cell Biol 6, 709–720 (2004). https://doi.org/10.1038/ncb1150

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