Differential role of the α1C subunit tails in regulation of the Cav1.2 channels by membrane potential ß subunits, and Ca2+ ions

Voltage-gated Ca(v)1.2 channels are composed of the pore-forming alpha(1C) and auxiliary beta and alpha(2)delta subunits. Voltage-dependent conformational rearrangements of the alpha(1C) subunit C-tail have been implicated in Ca2+ signal transduction. In contrast, the alpha(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 alpha(1C) subunit C-tail in the plasma membrane inhibits Ca2+-dependent and slow voltage-dependent inactivation. Both alpha(2)delta and beta subunits remain essential for the functional channel. In contrast, if alpha(1C) subunits are expressed with alpha(2)delta but in the absence of a beta subunit, plasma membrane anchoring of the alpha(1C) N terminus or its deletion inhibit both voltage- and Ca2+-dependent inactivation of the current. The following findings all corroborate the importance of the alpha(1C) N-tail/beta interaction: (i) coexpression of beta restores inactivation properties, (ii) release of the alpha(1C) N terminus inhibits the beta-deficient channel, and (iii) voltage-gated mobility of the alpha(1C) N-tail vis a vis the plasma membrane is increased in the beta-deficient ( silent) channel. Together, these data argue that both the alpha(1C) N- and C-tails have important but different roles in the voltage- and Ca2+-dependent inactivation, as well as beta subunit modulation of the channel. The alpha(1C) N-tail may have a role in the channel trafficking and is a target of the beta subunit modulation. The beta subunit facilitates voltage gating by competing with the N- tail and constraining its voltage- dependent rearrangements. Thus, cross-talk between the alpha(1C) C and N termini, beta subunit, and the cytoplasmic pore region confers the multifactorial regulation of Cav1.2 channels.