Internalization and recycling of the human prostacyclin receptor is modulated through its isoprenylation-dependent interaction with the delta subunit of cGMP phosphodiesterase 6

The Journal of Biological Chemistry
Stephen J Wilson, E M Smyth

Abstract

Prostacyclin, the major cyclooxygenase-derived product of arachidonic acid formed in the vasculature, mediates its potent anti-thrombotic and anti-proliferative effects through its G protein-coupled receptor (GPCR) termed the IP. Unlike many GPCRs, agonist-induced internalization of the IP occurs in an arrestin/GPCR kinase-independent manner. However, deletion of the IP COOH-terminal region prevented internalization suggesting that protein interactions at this region are involved in IP regulation. Using the COOH-terminal region of IP as bait we identified the delta subunit of cGMP phosphodiesterase 6 (PDE6delta) as a novel hIP-interacting protein in two independent yeast two-hybrid screens. Interaction of IP and PDE6delta was confirmed by co-immunoprecipitation in HEK293 cells, and in HEPG2 cells, which endogenously express neither IP nor PDE6delta. IP isoprenylation was critical for this interaction, as PDE6delta was unable to associate with an isoprenylation-deficient mutant IP (IPSSLC). PDE6delta overexpression altered the temporal pattern of agonist-induced internalization of IP, but not IPSSLC, in HEPG2 cells, increasing initial internalization but facilitating the return of IP to the cell surface despite the continued pre...Continue Reading

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Citations

Apr 19, 2011·Nature Chemical Biology·Christopher ChidleyKai Johnsson
Jan 30, 2013·Molecular and Cellular Biology·Akiyuki Nishimura, Maurine E Linder
Sep 13, 2012·Journal of Lipid Research·Elizebeth C Turner, B Therese Kinsella
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