Mechanism of auxiliary β ‐subunit‐mediated membrane targeting of L‐type (Ca V 1.2) channels

Non‐technical summary  Voltage‐dependent L‐type calcium (Ca V 1.2) channels are critical gateways for Ca 2+ entry into excitable cells such as heart myocytes and neurons. This Ca 2+ signal controls many essential physiological responses including triggering the heartbeat and regulating gene expression in nerve cells. Ca V 1.2 channels are multi‐subunit proteins, comprising α 1C , β, and α 2 δ subunits, and must target to the cell surface to function. Association of a pore‐forming α 1C and cytosolic β is necessary for targeting Ca V 1.2 channels to the cell surface through poorly understood mechanisms. Here, using a chimeric channel strategy, we provide data that suggest β binding to the α 1C intracellular I–II loop causes a global rearrangement of intracellular domains, shifting a balance of power between export signals on the I–II loop and retention signals elsewhere on the channel. The results provide novel insights into the mechanism of a protein–protein interaction that is vital for forming functional Ca V 1.2 channels.