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J Cell Biol. 2016 Mar 28;212(7):861-75. doi: 10.1083/jcb.201506132. Epub 2016 Mar 21.

Smoothened determines β-arrestin-mediated removal of the G protein-coupled receptor Gpr161 from the primary cilium.

Author information

1
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
2
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305.
3
Division of Biomedical Sciences, University of California, Riverside, Riverside, CA 92521.
4
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390 saikat.mukhopadhyay@utsouthwestern.edu.

Abstract

Dynamic changes in membrane protein composition of the primary cilium are central to development and homeostasis, but we know little about mechanisms regulating membrane protein flux. Stimulation of the sonic hedgehog (Shh) pathway in vertebrates results in accumulation and activation of the effector Smoothened within cilia and concomitant disappearance of a negative regulator, the orphan G protein-coupled receptor (GPCR), Gpr161. Here, we describe a two-step process determining removal of Gpr161 from cilia. The first step involves β-arrestin recruitment by the signaling competent receptor, which is facilitated by the GPCR kinase Grk2. An essential factor here is the ciliary trafficking and activation of Smoothened, which by increasing Gpr161-β-arrestin binding promotes Gpr161 removal, both during resting conditions and upon Shh pathway activation. The second step involves clathrin-mediated endocytosis, which functions outside of the ciliary compartment in coordinating Gpr161 removal. Mechanisms determining dynamic compartmentalization of Gpr161 in cilia define a new paradigm for down-regulation of GPCRs during developmental signaling from a specialized subcellular compartment.

PMID:
27002170
PMCID:
PMC4810300
DOI:
10.1083/jcb.201506132
[Indexed for MEDLINE]
Free PMC Article

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