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

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 (2007). Mechanism of Ca(v)1.2 channel modulation by the amino terminus of cardiac beta2-subunits. FASEB journal, 21(7), pp. 1527-38. Bethesda, Md.: Federation of American Societies for Experimental Biology 10.1096/fj.06-7377com

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Cardiovascular Disorders (DHGE) > Clinic of Cardiology

UniBE Contributor:

Hullin, Roger

ISSN:

0892-6638

ISBN:

17289923

Publisher:

Federation of American Societies for Experimental Biology

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:55

Last Modified:

04 May 2014 23:16

Publisher DOI:

10.1096/fj.06-7377com

PubMed ID:

17289923

Web of Science ID:

000246117000027

URI:

https://boris.unibe.ch/id/eprint/23249 (FactScience: 40705)

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