Differential role of the α_1C subunit tails in regulation of the Ca_v1.2 channel by membrane potential, β subunits, and Ca²⁺ ions

Voltage-gated Ca_v1.2 channels are composed of the pore-forming α_1C and auxiliary β and α₂δ subunits. Voltage-dependent conformational rearrangements of the α_1C subunit C-tail have been implicated in Ca²⁺ signal transduction. In contrast, the α_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 α_1C subunit C-tail in the plasma membrane inhibits Ca ²⁺-dependent and slow voltage-dependent inactivation. Both α₂δ and β subunits remain essential for the functional channel. In contrast, if α_1C subunits are expressed with α₂δ but in the absence of a β subunit, plasma membrane anchoring of the α_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 α_1C N-tail/β interaction: (i) co-expression of β restores inactivation properties, (ii) release of the α_1C N terminus inhibits the β-deficient channel, and (iii) voltage-gated mobility of the α_1C N-tail vis à vis the plasma membrane is increased in the β-deficient (silent) channel. Together, these data argue that both the α_1C N- and C-tails have important but different roles in the voltage- and Ca²⁺-dependent inactivation, as well as β subunit modulation of the channel. The α_1C N-tail may have a role in the channel trafficking and is a target of the β subunit modulation. The β subunit facilitates voltage gating by competing with the N-tail and constraining its voltage-dependent rearrangements. Thus, cross-talk between the α_1C C and N termini, β subunit, and the cytoplasmic pore region confers the multifactorial regulation of Ca _v1.2 channels.