Ca 2+ -Dependent Facilitation of Ca v 1.3 Ca 2+ Channels by Densin and Ca 2+ /Calmodulin-Dependent Protein Kinase II

Ca v 1 (L-type) channels and calmodulin-dependent protein kinase II (CaMKII) are key regulators of Ca 2+ signaling in neurons. CaMKII directly potentiates the activity of Ca v 1.2 and Ca v 1.3 channels, but the underlying molecular mechanisms are incompletely understood. Here, we report that the CaMKII-associated protein densin is required for Ca 2+ -dependent facilitation of Ca v 1.3 channels. While neither CaMKII nor densin independently affects Ca v 1.3 properties in transfected HEK293T cells, the two together augment Ca v 1.3 Ca 2+ currents during repetitive, but not sustained, depolarizing stimuli. Facilitation requires Ca 2+ , CaMKII activation, and its association with densin, as well as densin binding to the Ca v 1.3 α 1 subunit C-terminal domain. Ca v 1.3 channels and densin are targeted to dendritic spines in neurons and form a complex with CaMKII in the brain. Our results demonstrate a novel mechanism for Ca 2+ -dependent facilitation that may intensify postsynaptic Ca 2+ signals during high-frequency stimulation.