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Background  Increased activity of single ventricular L-type Ca 2+ -channels (L-VDCC) is a hallmark in human heart failure. Recent findings suggest differential modulation by several auxiliary β-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 β-subunit gene products. In HEK293-cells we show differential modulation of single L-VDCC activity by coexpression of several human cardiac β-subunits: Unlike β 1  or β 3  isoforms, β 2a  and β 2b  induce a high-activity channel behavior typical of failing myocytes. In accordance, β 2 -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 Ca V 1.2 also reveal increased single-channel activity and sarcolemmal β 2  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 β 2  expression. Additional evidence for the cause-effect relationship between β 2 -subunit expression and single L-VDCC activity is provided by newly engineered, double-transgenic mice bearing both constitutive Ca V 1.2 and inducible β 2  cardiac overexpression. Here in non-failing hearts induction of β 2 -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 β 2 -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.

Increased Expression of the Auxiliary β2-subunit of Ventricular L-type Ca2+ Channels Leads to Single-Channel Activity Characteristic of Heart Failure