Endocytosis of the Rat Somatostatin Receptors: Subtype Discrimination, Ligand Specificity, and Delineation of Carboxy-Terminal Positive and Negative Sequence Motifs

Roth, Adelheid; Kreienkamp, Hans‐Jürgen; Nehring, Ralf B.; Roosterman, Dirk; Meyerhof, Wolfgang; Richter, Dietmar

doi:10.1089/dna.1997.16.111

Cited by 72 publications

(104 citation statements)

References 25 publications

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“…Numerous mutagenesis studies have demonstrated that phosphorylation of serine and threonine residues in the Cterminal tail initiates receptor-mediated endocytosis (15,16,18,19). Nine putative S/T phosphorylation sites are deleted by the vl mutation (ca.expasy.org; McVector version 9.0), consistent with our endocytosis phenotype.…”

Section: Discussionsupporting

confidence: 77%

“…Gpr161 is expressed at all examined stages of lens development: lens pit (E10.5), lens vesicle (E11.5), primary lens Vl Mutation Affects Gpr161 Receptor-Mediated Endocytosis. Receptor-mediated endocytosis is a common mechanism by which GPCR signaling is attenuated and is regulated by C-terminal tail phosphorylation (15,16,18,19). To investigate the effects of the mutation on Gpr161 plasma membrane targeting and intracellular localization, WT and vl-myc-Gpr161 constructs were transfected into HEK293T cells.…”

Section: Resultsmentioning

confidence: 99%

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The orphan G protein-coupled receptor, Gpr161 , encodes the vacuolated lens locus and controls neurulation and lens development

Matteson

Desai

Korstanje

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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The vacuolated lens (vl) mouse mutant causes congenital cataracts and neural tube defects (NTDs), with the NTDs being caused by abnormal neural fold apposition and fusion. Our positional cloning of vl indicates these phenotypes result from a deletion mutation in an uncharacterized orphan G protein-coupled receptor (GPCR), Gpr161. Gpr161 displays restricted expression to the lateral neural folds, developing lens, retina, limb, and CNS. Characterization of the vl mutation indicates that C-terminal tail of Gpr161 is truncated, leading to multiple effects on the protein, including reduced receptor-mediated endocytosis. We have also mapped three modifier quantitative trait loci (QTL) that affect the incidence of either the vl cataract or NTD phenotypes. Bioinformatic, sequence, genetic, and functional data have determined that Foxe3, a key regulator of lens development, is a gene responsible for the vl cataract-modifying phenotype. These studies have extended our understanding of the vl locus in three significant ways. One, the cloning of the vl locus has identified a previously uncharacterized GPCR-ligand pathway necessary for neural fold fusion and lens development, providing insight into the molecular regulation of these developmental processes. Two, our QTL analysis has established vl as a mouse model for studying the multigenic basis of NTDs and cataracts. Three, we have identified Foxe3 as a genetic modifier that interacts with Gpr161 to regulate lens development.cataracts ͉ Foxe3 ͉ spina bifida

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Section: Discussionsupporting

confidence: 77%

Section: Resultsmentioning

confidence: 99%

The orphan G protein-coupled receptor, Gpr161 , encodes the vacuolated lens locus and controls neurulation and lens development

Matteson

Desai

Korstanje

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…SSTR5 was able to inhibit only the early phase of enzyme activation, allowing the late phase to occur unencumbered. From the literature, it appears that there are di¡er-ences in the cellular regulation of the ¢ve SSTRs and a di¡er-ent pattern of internalization has been described for each of them [12,13]. One can hypothesize that in our cells SSTR5 receptors may undergo a desensitization and internalization faster than the other two subtypes thus preventing a longterm action.…”

Section: Discussionmentioning

confidence: 80%

Selective stimulation of somatostatin receptor subtypes: differential effects on Ras/MAP kinase pathway and cell proliferation in human neuroblastoma cells

Cattaneo

Taylor²,

Culler³

et al. 2000

FEBS Letters

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In previous studies we have showed that somatostatin (SST) inhibits cell division, mitogen-activated protein (MAP) kinase and Ras activity in the human neuroblastoma cell line SY5Y. In the present study, we have assessed the role of a series of SST analogs, three of which were selective for SSTR1, SSTR2 or SSTR5, in these cellular events. All the analogs inhibited forskolin-induced cAMP accumulation. Selective stimulation of SSTR1 or SSTR2 but not of SSTR5 inhibited platelet-derived growth factor (PDGF)-induced [ 3 H]thymidine incorporation. The three analogs inhibited PDGF-stimulated MAP kinase activity, at least at an early time. In contrast, none of the analogs used individually was able to inhibit PDGFstimulated Ras activity. A combined stimulation of SSTR2 and SSTR5 was necessary to obtain a significant inhibitory effect, suggesting the possibility of receptor heterodimerization. These results indicate that SST inhibition of Ras and MAP kinase activities takes place via different pathways and that SST inhibition of PDGF-induced cell proliferation occurs via a Rasindependent pathway. ß

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“…All polyclonal rabbit antisera were purified by affinity chromatography using the Sulfo-Link coupling gel coupled to the appropriate immunizing peptide according to the instructions of the manufacturer (Pierce). Plasmid constructs of the rat sst 1 , sst 2A , sst 3 , sst 4 , and sst 5 containing the amino-terminal T7 epitope tag sequence MASMTGGQQMG in pcDNA3 have been described previously (13,15,21). Truncated sst 2A mutants were created by PCR using primers that introduce stop codons at suitable positions (22).…”

Section: Methodsmentioning

confidence: 99%

“…the rat sst 4 receptor appears to be largely resistant to agonist-induced internalization and desensitization (13), whereas the human sst 4 receptor has been reported to undergo a very slow but clearly detectable endocytosis. Other studies have shown that the human sst 1 receptor but not the rat sst 1 receptor failed to internalize in an agonist-dependent manner (14,15).…”

mentioning

confidence: 93%

Differential β-Arrestin Trafficking and Endosomal Sorting of Somatostatin Receptor Subtypes

Tulipano

Stumm

Pfeiffer

et al. 2004

Journal of Biological Chemistry

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152

146

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The physiological responses of somatostatin are mediated by five different G protein-coupled receptors. Although agonist-induced endocytosis of the various somatostatin receptor subtypes (sst 1 -sst 5 ) has been studied in detail, little is known about their postendocytic trafficking. Here we show that somatostatin receptors profoundly differ in patterns of ␤-arrestin mobilization and endosomal sorting. The ␤-arrestin-dependent trafficking of the sst 2A somatostatin receptor resembled that of a class B receptor in that upon receptor activation, ␤-arrestin and the receptor formed stable complexes and internalized together into the same endocytic vesicles. This pattern was dependent on GRK2 (G protein-coupled receptor kinase 2)-mediated phosphorylation of a cluster of phosphate acceptor sites within the cytoplasmic tail of the sst 2A receptor. Unlike other class B receptors, however, the sst 2A receptor was rapidly resensitized and recycled to the plasma membrane. The ␤-arrestin mobilization of the sst 3 and the sst 5 somatostatin receptors resembled that of a class A receptor in that upon receptor activation, ␤-arrestin and the receptor formed relatively unstable complexes that dissociated at or near the plasma membrane. Consequently, ␤-arrestin was excluded from sst 3 -containing vesicles. Unlike other class A receptors, a large proportion of sst 3 receptors was subject to ubiquitin-dependent lysosomal degradation and did not rapidly recycle to the plasma membrane. The sst 4 somatostatin receptor is unique in that it did not exhibit agonist-dependent receptor phosphorylation and ␤-arrestin recruitment. Together, these findings may provide important clues about the regulation of receptor responsiveness during long-term administration of somatostatin analogs.

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Endocytosis of the Rat Somatostatin Receptors: Subtype Discrimination, Ligand Specificity, and Delineation of Carboxy-Terminal Positive and Negative Sequence Motifs

Cited by 72 publications

References 25 publications

The orphan G protein-coupled receptor, Gpr161 , encodes the vacuolated lens locus and controls neurulation and lens development

The orphan G protein-coupled receptor, Gpr161 , encodes the vacuolated lens locus and controls neurulation and lens development

Selective stimulation of somatostatin receptor subtypes: differential effects on Ras/MAP kinase pathway and cell proliferation in human neuroblastoma cells

Differential β-Arrestin Trafficking and Endosomal Sorting of Somatostatin Receptor Subtypes

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