Subcellular sorting of the G-protein coupled mouse somatostatin receptor 5 by a network of PDZ-domain containing proteins

PLoS One. 2014 Feb 11;9(2):e88529. doi: 10.1371/journal.pone.0088529. eCollection 2014.

Abstract

PSD-95/discs large/ZO-1 (PDZ) domain proteins integrate many G-protein coupled receptors (GPCRs) into membrane associated signalling complexes. Additional PDZ proteins are involved in intracellular receptor trafficking. We show that three PDZ proteins (SNX27, PIST and NHERF1/3) regulate the mouse somatostatin receptor subtype 5 (SSTR5). Whereas the PDZ ligand motif of SSTR5 is not necessary for plasma membrane targeting or internalization, it protects the SSTR5 from postendocytic degradation. Under conditions of lysosomal inhibition, recycling of the SSTR5 to the plasma membrane does not depend on the PDZ ligand. However, recycling of the wild type receptor carrying the PDZ binding motif depends on SNX27 which interacts and colocalizes with the receptor in endosomal compartments. PIST, implicated in lysosomal targeting of some membrane proteins, does not lead to degradation of the SSTR5. Instead, overexpressed PIST retains the SSTR5 at the Golgi. NHERF family members release SSTR5 from retention by PIST, allowing for plasma membrane insertion. Our data suggest that PDZ proteins act sequentially on the GPCR at different stages of its subcellular trafficking.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Amino Acid Motifs
  • Animals
  • Biotinylation
  • Carrier Proteins / metabolism*
  • Cell Membrane / metabolism
  • Endocytosis
  • Endosomes / metabolism
  • Gene Expression Regulation*
  • Golgi Apparatus / metabolism
  • Golgi Matrix Proteins
  • HEK293 Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Ligands
  • Mice
  • PDZ Domains
  • Phosphoproteins / metabolism*
  • Protein Transport
  • Receptors, Somatostatin / metabolism*
  • Sodium-Hydrogen Exchangers / metabolism*
  • Sorting Nexins / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Golgi Matrix Proteins
  • Gopc protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Ligands
  • Phosphoproteins
  • Receptors, Somatostatin
  • Snx27 protein, mouse
  • Sodium-Hydrogen Exchangers
  • Sorting Nexins
  • sodium-hydrogen exchanger regulatory factor
  • somatostatin receptor 5

Grant support

This work was financially supported by Deutsche Forschungsgemeinschaft (Graduiertenkolleg GRK1459; to H.-J.K.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.