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J. Biol. Chem., Vol. 280, Issue 13, 12474-12485, April 1, 2005

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Differential Role of the _1C Subunit Tails in Regulation of the Ca_v1.2 Channel by Membrane Potential, Subunits, and Ca²+ Ions^*

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

From the Laboratory of Clinical Investigation and Cardiovascular Science, NIA, National Institutes of Health, Baltimore, Maryland 21224

Voltage-gated Ca_v1.2 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 Ca²⁺ 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 Ca²⁺-dependent and slow voltage-dependent inactivation. Both ₂ and subunits remain essential for the functional channel. In contrast, if _1C subunits with are expressed ₂ but in the absence of a subunit, plasma membrane anchoring of the _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 _1C N-tail/ interaction: (i) co-expression 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 N- and C-tails have important but different roles in the voltage- and Ca²⁺-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 Ca_v1.2 channels.

Received for publication, October 26, 2004 , and in revised form, January 18, 2005.

^* This work was supported by the National Institutes of Health, NIA Intramural Research Program. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Methods, Results and Discussion, Refs. 1–7, Fig. 1, and Table 1.

^¶ To whom correspondence should be addressed: Laboratory of Clinical Investigation, National Institute on Aging, 5600 Nathan Shock Dr., Baltimore, MD 21224. Tel.: 410-558-8343; Fax: 410-558-8318; E-mail: soldatovN{at}grc.nia.nih.gov.

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