Abstract
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 bg 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, phosphorylationindependent mechanism for rapidly downregulating GPCR activity at the effector level.
| Original language | English |
|---|---|
| Pages (from-to) | 750-760 |
| Number of pages | 11 |
| Journal | Cell |
| Volume | 143 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 24 Nov 2010 |
Funding
Josef Cohn Center for Biomembrane Research; Israeli Science Foundation (ISF) [207/09]; Minerva Foundation; Human Frontier Science ProgramThe authors like to thank Ruth Meller and Elisha Shalgi for technical help, and the Reuveny laboratory for helpful comments. We are grateful to Drs. J.L. Benovic for GRK2 and GRK6, W.C. Claycomb for HL-1 cells, D.E. Logothetis for PtdIns(4,5)P2 GIRK mutants, C. Barlot for G alpha<INF>s</INF> mutant, S. Nakanishi for the mGluR2, Z. Vogel for mu OR, and R. Tsien for mCherry cDNAs. The work was supported in part by the Josef Cohn Center for Biomembrane Research, The Israeli Science Foundation (ISF grant 207/09), The Minerva Foundation, and the Human Frontier Science Program.
All Science Journal Classification (ASJC) codes
- General Biochemistry,Genetics and Molecular Biology