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

Kasturi Pal, Sun hee Hwang, Bandarigoda Somatilaka, Hemant Badgandi, Peter K. Jackson, Kathryn DeFea, Saikat Mukhopadhyay

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42 Scopus citations


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 ß-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-ß-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.

Original languageEnglish (US)
Pages (from-to)861-875
Number of pages15
JournalJournal of Cell Biology
Issue number7
Publication statusPublished - Mar 28 2016


ASJC Scopus subject areas

  • Cell Biology

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