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Abstract Carvedilol is among the most effective β-blockers for improving survival after myocardial infarction. Yet the mechanisms by which carvedilol achieves this superior clinical profile are still unclear. Beyond blockade of β1-adrenoceptors, arrestin-biased signalling via β2-adrenoceptors is a molecular mechanism proposed to explain the survival benefits. Here, we offer an alternative mechanism to rationalize carvedilol’s cellular signalling. Using primary and immortalized cells genome-edited by CRISPR/Cas9 to lack either G proteins or arrestins; and combining biological, biochemical, and signalling assays with molecular dynamics simulations, we demonstrate that G proteins drive all detectable carvedilol signalling through β2ARs. Because a clear understanding of how drugs act is imperative to data interpretation in basic and clinical research, to the stratification of clinical trials or to the monitoring of drug effects on the target pathway, the mechanistic insight gained here provides a foundation for the rational development of signalling prototypes that target the β-adrenoceptor system.

Gq proteins are one of four major classes of G proteins; optogenetic receptors for selective and repetitive activation of Gq proteins with fast kinetics are lacking. Here the authors report UV light-dependent Gq signalling using human Neuropsin (hOPN5) and demonstrate its potential as an optogenetic tool.

Studying adrenergic signalling in the heart requires perfusion with receptor agonists, which lacks cell specificity and spatiotemporal control. Here the authors use the light sensitive G-coupled receptor JellyOp to optogenetically control Gs-signaling in cardiomyocytes and intact hearts with high spatiotemporal precision.

Abstract Ventricular tachycardia (VT) is the most common and potentially lethal complication following myocardial infarction (MI). Biological correction of the conduction inhomogeneity that underlies re-entry could be a major advance in infarction therapy. As minimal increases in conduction of infarcted tissue markedly influence VT susceptibility, we reasoned that enhanced propagation of the electrical signal between non-excitable cells within a resolving infarct might comprise a simple means to decrease post-infarction arrhythmia risk. We therefore tested lentivirus-mediated delivery of the gap-junction protein Connexin 43 (Cx43) into acute myocardial lesions. Cx43 was expressed in (myo)fibroblasts and CD45+ cells within the scar and provided prominent and long lasting arrhythmia protection in vivo. Optical mapping of Cx43 injected hearts revealed enhanced conduction velocity within the scar, indicating Cx43-mediated electrical coupling between myocytes and (myo)fibroblasts. Thus, Cx43 gene therapy, by direct in vivo transduction of non-cardiomyocytes, comprises a simple and clinically applicable biological therapy that markedly reduces post-infarction VT.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Abstract Improving equity is an emerging priority in climate and energy strategies, but little is known how these strategies would alter inequalities. Regional inequalities such as price, employment and land use are especially relevant in the electricity sector, which must decarbonize first to allow other sectors to decarbonize. Here, we show that a European low-carbon electricity sector in 2035 can reduce but also sustain associated regional inequalities. Using spatially-explicit modeling for 296 sub-national regions, we demonstrate that emission cuts consistent with net-zero greenhouse gas emissions in 2050 result in continent-wide benefits by 2035 regarding electricity sector investments, employment gains, and decreased greenhouse gas and particulate matter emissions. However, the benefits risk being concentrated in affluent regions of Northern Europe, while regions of Southern and Southeastern Europe risk high vulnerabilities due to high adverse impacts and sensitivities, and low adaptive capacities. Future analysis should investigate policy mechanisms for reducing and compensating inequalities.