Lethal shock is subverted by crippling a family of G proteins in endothelial cells, according to Korhonen and colleagues on page 411.

Bee stings or other allergens can cause anaphylactic shock in severely allergic individuals by triggering mast cell activation and the release of anaphylactic mediators like histamine and platelet activating factor (PAF). At high enough levels, these mediators cause blood pressure to drop precipitously and vessels to leak, eventually leading to shock. Although much is known about causes and consequences of anaphylaxis, the precise pathogenic pathways remain murky. Here, investigators find that shock was sidestepped in mice whose endothelia lacked the G protein go-betweens Gq/G11.

Many anaphylactic mediators act through G protein–coupled receptors, which link to downstream signaling molecules via G proteins, including Gq/G11, G12/G13, and Gi. Here, Gq/G11 turned out to be vital for opening the endothelial barrier and activating endothelial cells during an allergic reaction. Without Gq/G11, there was no phosphorylation of myosin light chain, which allows endothelial cells to retract from one another. Gq/G11 was also needed for the production of nitric oxide, a known mediator of anaphylactic shock.

On the other hand, endothelium-specific ablation of G12/G13, which activates the Rho/Rho-kinase pathway, had no effect on allergen-induced shock. And the effects of disabling Gi remain to be seen.

An endothelium-specific antagonist of a downstream player such as Gq/G11 could improve treatment for people at risk of allergen-induced shock. Epinephrine injections can be given only after anaphylaxis has begun, and upstream inhibitors of PAF have been ineffective. A pharmacological Gq/G11 inhibitor has already been developed and awaits testing in preclinical trials.