%0 Journal Article %1 Hullin2007 %A Hullin, R. %A Matthes, J. %A von Vietinghoff, S. %A Bodi, I. %A Rubio, M. %A D'Souza, K. %A Khan, I. Friedrich %A Rottlander, D. %A Hoppe, U. C. %A Mohacsi, P. %A Schmitteckert, E. %A Gilsbach, R. %A Bunemann, M. %A Hein, L. %A Schwartz, A. %A Herzig, S. %D 2007 %J PLoS One %K imported %N 3 %P e292 %T Increased expression of the auxiliary beta2-subunit of ventricular L-type Ca2+ channels leads to single-channel activity characteristic of heart failure %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17356701 %V 2 %X 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 (Ädaptive 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.

@article{Hullin2007, abstract = {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.}, added-at = {2010-12-14T18:12:02.000+0100}, author = {Hullin, R. and Matthes, J. and von Vietinghoff, S. and Bodi, I. and Rubio, M. and D'Souza, K. and Khan, I. Friedrich and Rottlander, D. and Hoppe, U. C. and Mohacsi, P. and Schmitteckert, E. and Gilsbach, R. and Bunemann, M. and Hein, L. and Schwartz, A. and Herzig, S.}, biburl = {https://www.bibsonomy.org/bibtex/204ce75d12c11c63480d42880954a3cfa/pharmawuerz}, endnotereftype = {Journal Article}, interhash = {00ecbd428a6a8ea29d507eb7c8d4b072}, intrahash = {04ce75d12c11c63480d42880954a3cfa}, issn = {1932-6203 (Electronic)}, journal = {PLoS One}, keywords = {imported}, note = {Hullin, Roger Matthes, Jan von Vietinghoff, Sibylle Bodi, Ilona Rubio, Marta D'Souza, Karen Friedrich Khan, Ismail Rottlander, Dennis Hoppe, Uta C Mohacsi, Paul Schmitteckert, Eva Gilsbach, Ralf Bunemann, Moritz Hein, Lutz Schwartz, Arnold Herzig, Stefan United States PloS one PLoS One. 2007 Mar 14;2(3):e292.}, number = 3, pages = {e292}, shorttitle = {Increased expression of the auxiliary beta2-subunit of ventricular L-type Ca2+ channels leads to single-channel activity characteristic of heart failure}, timestamp = {2010-12-14T18:12:15.000+0100}, title = {Increased expression of the auxiliary beta2-subunit of ventricular L-type Ca2+ channels leads to single-channel activity characteristic of heart failure}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17356701}, volume = 2, year = 2007 }