Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5509468 | Cellular Signalling | 2017 | 37 Pages |
Abstract
Recycling of the majority of agonist-internalized GPCR is dependent on a type I-PDZ “barcode” in their C-tail. The recycling of wild-type (WT) Ã1-AR is also dependent on its default “type-1 PDZ barcode”, but trafficking of the Ã1-AR is inhibited when PKA or its substrate serine at position 312 (Ser312) are inactivated. We tested the hypothesis that phospho-Ser312 provided a second barcode for Ã1-AR sorting from endosomes to the plasma membrane by determining the role of retromer/WASH complexes in Ã1-AR trafficking. Recycling of WT Ã1-AR or WT Ã2-AR was dependent on targeting the retromer to endosomal membranes via SNX3 and rab7a, and on complexing the retromer to the WASH pentamer via the C-tail of FAM21 (FAM21C). These maneuvers however, did not inhibit the recycling of a phospho-Ser312 Ã1-AR mimic ((S312D) Ã1-AR). Knockdown of the trans-acting PDZ protein sorting nexin27 (SNX27) inhibited the recycling of WT Ã1-AR and WT Ã2-AR, but had no effect on (S312D) Ã1-AR â PDZ or on phosphorylation of WT Ã1-AR by PKA at Ser312. However, depletion of FKBP15, a FAM21C-binding endosomal protein, selectively inhibited WT Ã1-AR but not Ã2-AR recycling, suggesting divergence might exist in GPCR trafficking roadmaps. These results indicate that two barcodes are involved in sorting WT Ã1-AR out of early endosomes. The first and antecedent “barcode” was the “type-1 PDZ”, followed by a second reversible “phospho-Ser312” verification “barcode”. This organization allows tight regulation of Ã1-AR density to signaling intensity in conditions associated with aberrant Ã1-AR signaling such as in hypertension and heart failure.
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Authors
Mohammed M. Nooh, Suleiman W. Bahouth,