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Voltage-Gated Rearrangements Associated with Differential ß-Subunit Modulation of the L-Type Ca²⁺ Channel Inactivation

Evgeny Kobrinsky ^*, Klaus J. F. Kepplinger , Alexander Yu ^*, Jo Beth Harry ^*, Heike Kahr , Christoph Romanin , Darrell R. Abernethy ^* and Nikolai M. Soldatov ^*

^* National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224 USA; and Institute for Biophysics, University of Linz, A-4040 Linz, Austria

Correspondence: Address reprints requests to N. M. Soldatov, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Dr., Baltimore, MD 21224. Tel.: 410-558-8343; Fax: 410-558-8318; E-mail: soldatovN{at}grc.nia.nih.gov.

Auxiliary ß-subunits bound to the cytoplasmic ₁-interaction domain of the pore-forming _1C-subunit are important modulators of voltage-gated Ca²⁺ channels. The underlying mechanisms are not yet well understood. We investigated correlations between differential modulation of inactivation by ß_1a- and ß₂- subunits and structural responses of the channel to transition into distinct functional states. The NH₂-termini of the _1C- and ß-subunits were fused with cyan or yellow fluorescent proteins, and functionally coexpressed in COS1 cells. Fluorescence resonance energy transfer (FRET) between them or with membrane-trapped probes was measured in live cells under voltage clamp. It was found that in the resting state, the tagged NH₂-termini of the _1C- and ß-subunit fluorophores are separated. Voltage-dependent inactivation generates strong FRET between _1C and ß_1a suggesting mutual reorientation of the NH₂-termini, but their distance vis-à-vis the plasma membrane is not appreciably changed. These voltage-gated rearrangements were substantially reduced when the ß_1a-subunit was replaced by ß₂. Differential ß-subunit modulation of inactivation and of FRET between _1C and ß were eliminated by inhibition of the slow inactivation. Thus, differential ß-subunit modulation of inactivation correlates with the voltage-gated motion between the NH₂-termini of _1C- and ß-subunits and targets the mechanism of slow voltage-dependent inactivation.

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