Increased expression of the auxiliary β2-subunit of ventricular L-type Ca2+ channels leads to enhanced single-channel activity characteristic of failing cardiomyocytes.
Does increased expression of auxiliary beta2-subunits alter single ventricular L-type Ca2+ channel activity in models of heart failure?
Increased expression of the auxiliary beta2-subunit of ventricular L-type Ca2+ channels is a key pathobiochemical mechanism driving the altered single-channel gating observed in heart failure.
Absolute Event Rate: 228% vs 213%
p-value: p=<0.05
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 beta-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 beta-subunit gene products. In HEK293-cells we show differential modulation of single L-VDCC activity by coexpression of several human cardiac beta-subunits: Unlike beta(1) or beta(3) isoforms, beta(2a) and beta(2b) induce a high-activity channel behavior typical of failing myocytes. In accordance, beta(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 beta(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 beta(2) expression. Additional evidence for the cause-effect relationship between beta(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 beta(2) cardiac overexpression. Here in non-failing hearts induction of beta(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 beta(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.
Hullin et al. (Tue,) conducted a other in Heart Failure (n=13). Heart failure state / β2-subunit overexpression vs. Non-failing myocardium / Wild-type was evaluated on Peak ensemble average current (I peak) of single L-VDCC in human failing vs non-failing ventricle (fA) (p=<0.05). Increased expression of the auxiliary β2-subunit of ventricular L-type Ca2+ channels leads to enhanced single-channel activity characteristic of failing cardiomyocytes.