Mice with cardiac-specific sequestration of the β-subunit of the L-type calcium channel

Author： Serikov V.   Bodi I.   Koch S.E.   Muth J.N.   Mikala G.   Martinov S.G.   Haase H.   Schwartz A.  

Publisher： Elsevier

ISSN： 0006-291X

Source： Biochemical and Biophysical Research Communications, Vol.293, Iss.5, 2002-05, pp. : 1405-1411

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Abstract

The βsubunit of the L-type voltage-dependent calcium channel modifies the properties of the channel complex by both allosteric modulation of theα1 subunit function and by chaperoning the translocation of theα1 subunit to the plasma membrane. The goal of this study was to investigate the functional effect of changing the in vivo stoichiometry between theα1 andβ subunits by creating a dominant negative expression system in a transgenic mouse model. The high affinity β subunit-binding domain of the α1subunit was overexpressed in a cardiac-specific manner to act as aβ subunit trap. We found that the predominant β isoform was located primarily in the membrane bound fraction of heart protein, whereas theβ1 andβ3 were mostly cytosolic. There was a significant diminution of the amount ofβ2 in the membrane fraction of the transgenic animals, resulting in a decrease in contractility of the heart and a decrease in L-type calcium current density in the myocyte. However, there were no distinguishable differences inβ1 andβ3 protein expression levels in the membrane bound fraction between transgenic and non-transgenic animals. Since the β1and β3 isoforms only make up a small portion of the totalβ subunit in the heart, slight changes in this fraction are not detectable using Western analysis. In contrast, β1 andβ3 in skeletal muscle and brain, the predominant isoforms in these tissues, respectively, are membrane bound.© 2002 Elsevier Science (USA)

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