A molecular mechanism to diversify Ca signaling downstream of Gs protein-coupled receptors.

A long-held tenet in inositol-lipid signaling is that cleavage of membrane phosphoinositides by phospholipase Cβ (PLCβ) isozymes to increase cytosolic Ca in living cells is exclusive to Gq- and Gi-sensitive G protein-coupled receptors (GPCRs). Here we extend this central tenet and show that Gs-GPCRs also partake in inositol-lipid signaling and thereby increase cytosolic Ca. By combining CRISPR/Cas9 genome editing to delete Gα, the adenylyl cyclase isoforms 3 and 6, or the PLCβ1-4 isozymes, with pharmacological and genetic inhibition of Gq and G11, we pin down Gs-derived Gβγ as driver of a PLCβ2/3-mediated cytosolic Ca release module.

Giving ERK a jERK from the endosome.

Endosomes, long considered as sorting stations for downregulation and recycling of cell surface G protein-coupled receptors (GPCRs), are now well-established sites of signal transduction. Recent work from the groups of Jin Zhang and Roger Sunahara features endosomes as signaling hubs and physical platforms for noncanonical activation of ERK by GPCRs.

How Carvedilol activates β-adrenoceptors.

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 β-adrenoceptors, arrestin-biased signalling via β-adrenoceptors is a molecular mechanism proposed to explain the survival benefits.

Humanized zebrafish as a tractable tool for in vivo evaluation of pro-myelinating drugs.

Therapies that promote neuroprotection and axonal survival by enhancing myelin regeneration are an unmet need to prevent disability progression in multiple sclerosis. Numerous potentially beneficial compounds have originated from phenotypic screenings but failed in clinical trials. It is apparent that current cell- and animal-based disease models are poor predictors of positive treatment options, arguing for novel experimental approaches.