Mechanism of Ca(v)1.2 channel modulation by the amino terminus of cardiac beta(2)-subunits

作者：Herzig Stefan^*; Khan Ismail F Y; Gruendemann Dirk; Matthes Jan; Ludwig Andreas; Michels Guido; Hoppe Uta C; Chaudhuri Dipayan; Schwartz Arnold; Yue David T; Hullin Roger

来源：The FASEB Journal, 2007, 21(7): 1527-1538.

DOI：10.1096/fj.06-7377com

• cardiac electrophysiology
• calcium channel subunit
• dihydropyridine

L- type calcium channels are composed of a pore, alpha(1c) ( Ca(v)1.2), and accessory beta- and alpha(2)delta-subunits. The beta(2)-subunit core structure was recently resolved at high resolution, providing important information on many functional aspects of channel modulation. In this study we reveal differential novel effects of five beta(2)-subunits isoforms expressed in human heart (beta(2a-e)) on the single L- type calcium channel current. These splice variants differ only by amino- terminal length and amino acid composition. Single- channel modulation by beta(2)-subunit isoforms was investigated in HEK293 cells expressing the recombinant L- type ion conducting pore. All beta(2)- subunits increased open probability, availability, and peak current with a highly consistent rank order (beta(2a) approximate to beta(2b) > beta(2e) approximate to beta(2c) > beta(2d)). We show graded modulation of some transition rates within and between deep- closed and inactivated states. The extent of modulation correlates strongly with the length of amino- terminal domains. Two mutant beta(2)-subunits that imitate the natural span related to length confirm this conclusion. The data show that the length of amino termini is a relevant physiological mechanism for channel closure and inactivation, and that natural alternative splicing exploits this principle for modulation of the gating properties of calcium channels.

• 出版日期2007-5