Ca 2+ channel moving tail: link between Ca 2+-induced inactivation and Ca 2+ signal transduction

Abstract

Ca 2+-induced inactivation is an important property of L-type voltage-gated Ca 2+ channels. However, the underlying mechanisms are not yet understood well. There is general agreement that calmodulin (CaM) binds, in a Ca 2+-dependent manner, to C-terminal motifs LA and IQ of the pore-forming α1 c-subunit and acts as a sensor that conveys Ca 2+-induced inactivation. New data indicate that both Ca 2+-induced inactivation and Ca 2+ signal transduction depend on the voltage-gated mobility of the C-terminal tail of the α1 c-subunit. It is proposed that LA is a Ca 2+-sensitive lock for the mechanism of slow voltage-dependent inactivation of the channel. A Ca 2+-dependent switch of CaM from LA to IQ removes CaM from the inner mouth of the pore and thus eliminates slow inactivation by facilitating the constriction of the pore. The mobile tail then shuttles the Ca 2+–CaM–IQ complex to a downstream target of the Ca 2+ signaling cascade, where Ca 2+ is released as an activating stimulus. Apo–CaM rebinds to LA and returns to the pore for a new cycle of Ca 2+ signal transduction.