Increased expression of the auxiliary beta(2)-subunit of ventricular L-type Ca(2)+ channels leads to single-channel activity characteristic of heart failure.
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.


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
Roger
R
Department of Cardiology, Swiss Heart Center Bern, University Hospital, Bern, Switzerland. roger.hullin@insel.ch
Matthes
Jan
J
von Vietinghoff
Sibylle
S
Bodi
Ilona
I
Rubio
Marta
M
D'Souza
Karen
K
Friedrich Khan
Ismail
I
Rottländer
Dennis
D
Hoppe
Uta C
UC
Mohacsi
Paul
P
Schmitteckert
Eva
E
Gilsbach
Ralf
R
Bünemann
Moritz
M
Hein
Lutz
L
Schwartz
Arnold
A
Herzig
Stefan
S
D000375:Aging / Q000502:physiology; D000818:Animals; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000502:physiology*; D002908:Chronic Disease; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000235:genetics*; D006352:Heart Ventricles / Q000503:physiopathology*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype
D020746:Calcium Channels, L-Type