%0 Journal Article
%T Increased Expression of the Auxiliary ¦Â2-subunit of Ventricular L-type Ca2+ Channels Leads to Single-Channel Activity Characteristic of Heart Failure
%A Roger Hullin
%A Jan Matthes
%A Sibylle von Vietinghoff
%A Ilona Bodi
%A Marta Rubio
%A Karen D'Souza
%A Ismail Friedrich Khan
%A Dennis Rottl£¿nder
%A Uta C. Hoppe
%A Paul Mohacsi
%A Eva Schmitteckert
%A Ralf Gilsbach
%A Moritz B¨¹nemann
%A Lutz Hein
%A Arnold Schwartz
%A Stefan Herzig
%J PLOS ONE
%D 2007
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0000292
%X Background Increased activity of single ventricular L-type Ca2+-channels (L-VDCC) is a hallmark in human heart failure. Recent findings suggest differential modulation by several auxiliary ¦Â-subunits as a possible explanation. Methods and Results By molecular and functional analyses of human and murine ventricles, we find that enhanced L-VDCC activity is accompanied by altered expression pattern of auxiliary L-VDCC ¦Â-subunit gene products. In HEK293-cells we show differential modulation of single L-VDCC activity by coexpression of several human cardiac ¦Â-subunits: Unlike ¦Â1 or ¦Â3 isoforms, ¦Â2a and ¦Â2b induce a high-activity channel behavior typical of failing myocytes. In accordance, ¦Â2-subunit mRNA and protein are up-regulated in failing human myocardium. In a model of heart failure we find that mice overexpressing the human cardiac CaV1.2 also reveal increased single-channel activity and sarcolemmal ¦Â2 expression when entering into the maladaptive stage of heart failure. Interestingly, these animals, when still young and non-failing (¡°Adaptive Phase¡±), reveal the opposite phenotype, viz: reduced single-channel activity accompanied by lowered ¦Â2 expression. Additional evidence for the cause-effect relationship between ¦Â2-subunit expression and single L-VDCC activity is provided by newly engineered, double-transgenic mice bearing both constitutive CaV1.2 and inducible ¦Â2 cardiac overexpression. Here in non-failing hearts induction of ¦Â2-subunit overexpression mimicked the increase of single L-VDCC activity observed in murine and human chronic heart failure. Conclusions Our study presents evidence of the pathobiochemical relevance of ¦Â2-subunits for the electrophysiological phenotype of cardiac L-VDCC and thus provides an explanation for the single L-VDCC gating observed in human and murine heart failure.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0000292