Seeing β-arrestin in action: The role of β-arrestins in Histamine 1 Receptor signaling

{beta}-arrestins regulate G protein-coupled receptor functions by influencing their signaling activity and intracellular location. Histamine is a major chemical mediator of allergic reactions, and its action is mainly mediated by the Gq/11- and Gi-coupled H1R. Contrary to accumulating insights into G protein-mediated signaling downstream of H1R, very little is known about the function of {beta}-arrestins in H1R signaling. Here, we describe dynamic, live cell measurements of {beta}-arrestin recruitment upon H1R activation in HEK293TN cells. Our observations classify H1R as a class A receptor, undergoing transient interactions with {beta}-arrestin. To investigate the relative contributions of G proteins and {beta}-arrestins to H1R signaling, we use specific G protein inhibitors, as well as {beta}-arrestin overexpression and depletion, and quantify various signaling outcomes in a panel of dynamic, live cell biosensor assays. Overall, we link {beta}-arrestins to desensitization of H1R-mediated signaling and show that ERK activation downstream of endogenous (HeLa, HUVEC) or transiently expressed (HEK293TN) H1R is largely Gq-mediated.