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.
Highlights
Signalling by G-protein coupled receptors (GPCRs) is controlled by a variety of cellular mechanisms
We have recently shown that it interacts with the PSD-95/discs large/ZO-1 (PDZ) domains of the Golgi-associated protein PIST as well as the scaffold protein NHERF3/PDZ-K1 via its C-terminal PDZ ligand motif [8,15]
Role of the PDZ ligand motif in receptor turnover We analyzed whether the PDZ ligand motif of the somatostatin receptor subtype 5 (SSTR5) affects the stability of the receptor, assuming that an eventual targeting of the receptor to the lysosome by PIST would be affected by loss of the PDZ binding motif at the C-terminus of the receptor
Summary
Signalling by G-protein coupled receptors (GPCRs) is controlled by a variety of cellular mechanisms. PDZ domain containing proteins are typically soluble, cytoplasmic proteins which associate with C-terminal PDZ-ligand motifs of membrane proteins [5]. Other proteins containing multiple interaction motifs such as PSD-95, MUPP1 or NHERF family members act as scaffolds by integrating GPCRs into larger protein complexes at the plasma membrane [2,11,12,13]. It is unclear whether these receptor/scaffold protein complexes are formed spontaneously at the plasma membrane, or whether they are preformed early in the biosynthetic pathway of the receptor, and transported to the plasma membrane
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