pe, viz: reduced single-channel activity accompanied by lowered b2 expression. 15272207 Additional evidence for the cause-effect relationship between b2-subunit expression and single L-VDCC activity is provided by newly engineered, double-transgenic mice bearing both constitutive CaV1.2 and inducible b2 cardiac overexpression. Here in non-failing hearts induction of b2-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 b2-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. Citation: Hullin R, Matthes J, von Vietinghoff S, Bodi I, Rubio M, et al Increased Expression of the Auxiliary b2-subunit of Ventricular L-type Ca2+ Channels Leads to Single-Channel Activity Characteristic of Heart Failure. PLoS ONE 2: e292. doi:10.1371/journal.pone.0000292 INTRODUCTION Homeostasis of intracellular Ca concentration i is essential for cardiac function and integrity; its dysregulation is a hallmark of advanced heart failure. Voltage-dependent L-type Ca2+channels are the source of trigger Ca2+ entering cardiomyocytes. Data derived from numerous studies support an involvement of L-VDCC in pathological changes of i in heart failure. Although still controversial, L-VDCC current WP 1130 site density appears unchanged in failing cardiomyocytes. Whole-cell currents are determined by a number of parameters, including number 
of channels, single-channel current amplitude and time spent in the open state. Therefore, altered number of active channels or activity of individual L-VDCC is not necessarily reflected by calcium current density. In fact, despite no change in whole-cell L-VDCC density, single-channel activity was significantly increased in ventricular myocytes from human endstage failing hearts. Chen et al. showed attenuated ICa increase by -BayK8644 in human failing myocardium whereas basal whole-cell currents were unchanged, indicating that singlechannel activity is 16041400 enhanced while channel density is lowered. These findings confirm the idea of an electrophysiological heartfailure phenotypeof single L-VDCCs. The biochemical nature of this change in phenotype has not been delineated, although phosphorylation and dephosphorylation have been implicated. Activities of kinases and phosphatases not only change channel function but interfere with neurohumoral modulation of the L-VDCC; e.g. b-adrenergic regulation is blunted in heart 2+ 2+ failure possibly due to hyperphosphorylation of L-VDCCs. Using heterologous recombination we have shown that distinct subunit compositions of L-VDCC induce single-channel characteristics similar to the biophysical phenotype of hyperphosphorylatedL-VDCC. The latter suggests that changes in gene expression of L-VDCC subunits may form the basis of a heart-failure phenotype of L-VDCC. In mammalian hearts LVDCCs are composed of an ion conducting pore, and two auxiliary subunits, an a2d and a b-subunit. Most Academic Editor: Andrew Jenkins, Emory University, United States of America Received November 29, 2006; Accepted February 19, 2007; Published March 14, 2007 Copyright: 2007 Hullin et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original