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

Evgeny Kobrinsky, Swasti Tiwari, Victor A. Maltsev, Jo Beth Harry, Edward Lakatta, Darrell R. Abernethy, Nikolai M. Soldatov

Research output: Contribution to journalArticlepeer-review

Abstract

Voltage-gated Cav1.2 channels are composed of the pore-forming α1C and auxiliary β and α2δ subunits. Voltage-dependent conformational rearrangements of the α1C subunit C-tail have been implicated in Ca2+ signal transduction. In contrast, the α1C 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 α1C 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 α1C subunits are expressed with α2δ but in the absence of a β subunit, plasma membrane anchoring of the α1C N terminus or its deletion inhibit both voltage- and Ca2+-dependent inactivation of the current. The following findings all corroborate the importance of the α1C N-tail/β interaction: (i) co-expression of β restores inactivation properties, (ii) release of the α1C N terminus inhibits the β-deficient channel, and (iii) voltage-gated mobility of the α1C N-tail vis à vis the plasma membrane is increased in the β-deficient (silent) channel. Together, these data argue that both the α1C 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 α1C 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 α1C C and N termini, β subunit, and the cytoplasmic pore region confers the multifactorial regulation of Ca v1.2 channels.

Original languageEnglish (US)
Pages (from-to)12474-12485
Number of pages12
JournalJournal of Biological Chemistry
Volume280
Issue number13
DOIs
StatePublished - Apr 1 2005

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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