Nonenzymatic Rapid Control of GIRK Channel Function by a G Protein-Coupled Receptor Kinase

SummaryG protein-coupled receptors (GPCRs) respond to agonists to activate downstream enzymatic pathways or to gate ion channel function. Turning off GPCR signaling is known to involve phosphorylation of the GPCR by GPCR kinases (GRKs) to initiate their internalization. The process, however, is relatively slow and cannot account for the faster desensitization responses required to regulate channel gating. Here, we show that GRKs enable rapid desensitization of the G protein-coupled potassium channel (GIRK/Kir3.x) through a mechanism independent of their kinase activity. On GPCR activation, GRKs translocate to the membrane and quench channel activation by competitively binding and titrating G protein βγ subunits away from the channel. Of interest, the ability of GRKs to effect this rapid desensitization depends on the receptor type. The findings thus reveal a stimulus-specific, phosphorylation-independent mechanism for rapidly downregulating GPCR activity at the effector level.

Graphical AbstractFigure optionsDownload high-quality image (300 K)Download as PowerPoint slideHighlights
► Rapid desensitization of GIRK channels depends on GRK2
► This function of GRK2 is independent of its kinase activity
► GRK2 competitively binds Gβγ, titrating it from the channel
► This phosphorylation-independent mechanism allows rapid turn-off of GPCR activity