Voltage gated Ca 2+ channels are major routes for the entry of intracellular Ca 2+ coupled to membrane depolarization that appear to vary greatly with respect to their voltage dependence and kinetics. Such variability maybe in part related to the attached signaling properties of the channel, in addition to the transport of calcium. In the present review we consider the possible role of calcium-dependent inactivation of Ca v 1.2 in Ca 2+ signal transduction and signaling of calcium release from the cardiac sarcoplasmic reticulum. We explore the specific roles of Ca 2+ -sensing calmodulin-binding domains of the C-terminal tail (LA and K) of the channel in mediating Ca 2+ -induced Ca 2+ release and signal transduction. Our experiments point to an intriguing possibility that the C-terminal tail of Ca v 1.2 may translocate the Ca 2+ signal as a part of inactivation mechanism and the corresponding voltage-gated rearrangement of the C-terminus. We show how a dynamic and transient regulation, in a Ca 2+ -dependent manner, defines molecular events including Ca 2+ release and signaling of cAMP-responsive element-binding protein (CREB)-dependent transcription. We propose that such Ca 2+ -dependent C-tail translocation that also initiates the channel inactivation, may have evolved specifically for the Ca v 1.2 channel.