Nonenzymatic rapid control of GIRK channel function by a G protein-coupled receptor kinase.
G 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.
Department Biological Chemistry Weizmann Institute of Science, Rehovot, Israel.
Adi
A
Raveh
Ayelet
A
Cooper
Liora
L
Guy-David
Eitan
E
Reuveny
D000818:Animals; D002468:Cell Physiological Phenomena; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000737:chemistry / Q000378:metabolism*; D054768:G-Protein-Coupled Receptor Kinases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D010766:Phosphorylation
D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C497069:Kcnj6 protein, mouse; D054768:G-Protein-Coupled Receptor Kinases