Differential Role of the 1 C Subunit Tails in Regulation of the Cav 1 . 2 Channel by Membrane Potential , Subunits , and Ca 2 Ions

Voltage-gated Cav1.2 channels are composed of the pore-forming 1C and auxiliary and 2 subunits. Voltage-dependent conformational rearrangements of the 1C subunit C-tail have been implicated in Ca 2 signal transduction. In contrast, the 1C N-tail demonstrates limited voltage-gated mobility. We have asked whether these properties are critical for the channel function. Here we report that transient anchoring of the 1C subunit C-tail in the plasma membrane inhibits Ca 2 dependent and slow voltage-dependent inactivation. Both 2 and subunits remain essential for the functional channel. In contrast, if 1C subunits are expressed with 2 but in the absence of a subunit, plasma membrane anchoring of the 1C N terminus or its deletion inhibit both voltageand Ca -dependent inactivation of the current. The following findings all corroborate the importance of the 1C N-tail/ interaction: (i) coexpression of restores inactivation properties, (ii) release of the 1C N terminus inhibits the -deficient channel, and (iii) voltage-gated mobility of the 1C N-tail vis à vis the plasma membrane is increased in the -deficient (silent) channel. Together, these data argue that both the 1C Nand C-tails have important but different roles in the voltageand Ca -dependent inactivation, as well as subunit modulation of the channel. The 1C N-tail may have a role in the channel trafficking and is a target of the subunit modulation. The subunit facilitates voltage gating by competing with the N-tail and constraining its voltage-dependent rearrangements. Thus, cross-talk between the 1C C and N termini, subunit, and the cytoplasmic pore region confers the multifactorial regulation of Cav1.2 channels.