Details

Autor(en) / Beteiligte

• Herzig, Stefan
• Khan, Ismail F Y
• Gründemann, Dirk
• Matthes, Jan
• Ludwig, Andreas
• Michels, Guido
• Hoppe, Uta C
• Chaudhuri, Dipayan
• Schwartz, Arnold
• Yue, David T
• Hullin, Roger

Titel

Mechanism of Ca(v)1.2 channel modulation by the amino terminus of cardiac beta2-subunits

Ist Teil von

• The FASEB journal, 2007-05, Vol.21 (7), p.1527-1538

Ort / Verlag

United States

Erscheinungsjahr

2007

Quelle

Wiley Online Library Journals Frontfile Complete

Beschreibungen/Notizen

• L-type calcium channels are composed of a pore, alpha1c (Ca(V)1.2), and accessory beta- and alpha2delta-subunits. The beta-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 beta2-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 beta2-subunit isoforms was investigated in HEK293 cells expressing the recombinant L-type ion conducting pore. All beta2-subunits increased open probability, availability, and peak current with a highly consistent rank order (beta2a approximately = beta2b > beta2e approximately = beta2c > beta2d). 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 beta2-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.