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Mechanism of Ca_v1.2 channel modulation by the amino terminus of cardiac ß₂-subunits

Stefan Herzig^*,,1,2, Ismail F. Y. Khan^*,,1, Dirk Gründemann^*,, Jan Matthes^*, Andreas Ludwig, Guido Michels^¶, Uta C. Hoppe^¶,, Dipayan Chaudhuri, Arnold Schwartz^||, David T. Yue and Roger Hullin^**

^* Department of Pharmacology, University of Cologne, Cologne, Germany,

Center of Molecular Medicine, University of Cologne, Cologne, Germany;

Institute of Experimental and Clinical Pharmacology and Toxicology, University Erlangen-Nuernberg, Erlangen, Germany;

^¶ Internal Medicine III, University of Cologne, Cologne, Germany;

Johns Hopkins University School of Medicine, Baltimore, Maryland, USA;

^|| Institute of Molecular Pharmacology and Biophysics, University of Cincinnati, Cincinnati, Ohio, USA; and

^** Department of Cardiology, Swiss Heart Center Bern, University Hospital, Bern, Switzerland

²Correspondence: Department of Pharmacology, University of Cologne, Gleueler Strasse 24, 50931 Köln, Germany. E-mail: stefan.herzig{at}uni-koeln.de

L-type calcium channels are composed of a pore, _1c (Ca_V1.2), and accessory ß- and ₂-subunits. The ß-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 ß₂-subunits isoforms expressed in human heart (ß_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 ß₂-subunit isoforms was investigated in HEK293 cells expressing the recombinant L-type ion conducting pore. All ß₂-subunits increased open probability, availability, and peak current with a highly consistent rank order (ß_2aß_2b>ß_2eß_2c>ß_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 ß₂-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.—Herzig, S., Khan, I. F. Y., Gründemann, D., Matthes, J., Ludwig, A., Michels, G., Hoppe, U. C., Chaudhuri, D., Schwartz, A., Yue, D. T., Hullin, R. Mechanism of Ca_v1.2 channel modulation by the amino terminus of cardiac ß₂-subunits.

Key Words: cardiac electrophysiology • calcium channel subunit • dihydropyridine