CaVβ controls the endocytic turnover of CaV1.2 L‐type calcium channel. (5th May 2021) - Conrad, Rachel
Abstract: Membrane depolarization activates the multisubunit CaV 1.2 L‐type calcium channel initiating various excitation coupling responses. Intracellular trafficking into and out of the plasma membrane regulates the channel's surface expression and stability, and thus, the strength of CaV 1.2‐mediated Ca 2+ signals. The mechanisms regulating the residency time of the channel at the cell membrane are unclear. Here, we coexpressed the channel core complex CaV 1.2α1 pore‐forming and auxiliary CaV β subunits and analyzed their trafficking dynamics from single‐particle‐tracking trajectories. Speed histograms obtained for each subunit were best fitted to a sum of diffusive and directed motion terms. The same mean speed for the highest‐mobility state underlying directed motion was found for all subunits. The frequency of this component increased by covalent linkage of CaV β to CaV 1.2α1 suggesting that high‐speed transport occurs in association with CaV β. Selective tracking of CaV 1.2α1 along the postendocytic pathway failed to show the highly mobile state, implying CaV β‐independent retrograde transport. Retrograde speeds of CaV 1.2α1 are compatible with myosin VI‐mediated backward transport. Moreover, residency time at the cell surface was significantly prolonged when CaV 1.2α1 was covalently linked to CaV β. Thus, CaV β promotes fast transport speed along anterograde trafficking and acts as a molecular switch controlling the endocytic turnover of L‐type calcium channels. Abstract : The amount of calcium channels at the plasma membrane regulates the amplitude of Ca 2+ entry and downstream Ca 2+ signals. Live‐cell imaging and trajectory analysis of CaV 1.2 pore‐forming subunit and its CaV β‐subunit, show that CaV β promotes high‐speed anterograde transport and increases the channel's residency time at the cell surface. Back from the plasma membrane CaV β‐free channels are transported slower, compatible with actin motor Myosin VI speed. Therefore, by favoring one trafficking direction, CaV β fine‐tunes the surface expression of L‐type calcium channels.