Subcellular Sorting of the G-Protein Coupled Mouse Somatostatin Receptor 5 by a Network of PDZ-Domain Containing Proteins

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.

A defect in the retromer accessory protein, SNX27, manifests by infantile myoclonic epilepsy and neurodegeneration

“…Cargo proteins for SNX27-mediated sorting include the Menkes disease-associated copper transport ATP7A, the glucose transporter GLUT1, various metal and amino acid transporters, ion channels and numerous signaling receptors [31,32,29,25,33,28,34] that include the β2-adrenergic receptor [30,10], and the ionotropic glutamate receptors α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPA-R) and Nmethyl-D-aspartate (NMDA) receptor (NMDA-R) [35][36][37][38]. With such a central role in controlling the cell surface levels of functionally diverse transmembrane proteins, it is not surprising that SNX27 homozygous knockoutmice are born with a non-Mendelian frequency, suggestive of in utero defects in embryonic development, and for those mice that are born, they are weaker and smaller than their littermates, display abnormal behavior and die within 4 weeks of birth [35].…”

PDZ Protein Regulation of G Protein–Coupled Receptor Trafficking and Signaling Pathways

“…In contrast, NHERF1 increases thromboxane receptor b cell surface expression by blocking the internalization of the receptor (Rochdi and Parent, 2003). An additional mechanism by which NHERF1 may increase GPCR membrane targeting is via its competition with the cystic fibrosis transmembrane conductance regulatorassociated ligand (CAL) to antagonize CAL-mediated retention of GPCRs in the Golgi (Bauch et al, 2014).…”

“…CAL reduces plasma membrane expression and recycling of b 1 AR, and interferes with both b 1 AR-mediated ERK signaling and postendocytotic receptor degradation via the lysosome (He et al, 2004;Koliwer et al, 2015). CAL overexpression retains SSTR5 in the Golgi apparatus, thereby reducing SSTR5 cell surface expression (Wente et al, 2005;Bauch et al, 2014). Additionally, CAL colocalizes with mGluR1a following agonist activation, and its overexpression decreases mGluR1a-stimulated ERK signaling (Zhang et al, 2008b).…”

“…SNX27 interacts with both serotonin 4A receptor and b 2 AR in early endosome antigen 1-positive early endosomes (Joubert et al, 2004;Lauffer et al, 2010). Moreover, SNX27 is involved in regulating the recycling of b 2 AR, b 1 AR, and SSTR5, thereby preventing receptor degradation (Lauffer et al, 2010;Temkin et al, 2011;Nakagawa and Asahi, 2013;Bauch et al, 2014). The regulation of b 2 AR recycling by SNX27 is dependent upon Phox homology domain-mediated associations with the endosomal membrane (Lauffer et al, 2010).…”

The Golgi-associated PDZ Domain Protein PIST/GOPC Stabilizes the β1-Adrenergic Receptor in Intracellular Compartments after Internalization

“…C-terminal PSD-95/discs large/ZO-1 (PDZ) ligand motifs, which enable selected receptors to bind to PDZ domain-containing proteins, have been established as important determinants for recycling (4) or degradation (6). Whereas some PDZ domain proteins serve as scaffolds for GPCR-associated signaling complexes at the plasma membrane (7,8), it is now becoming clear that receptors are handed over to other PDZ domain proteins during their passage through intracellular compartments (9). Several recent studies have now begun to elucidate PDZ domain-containing proteins that are involved in postendocytic sorting.…”