scholarly journals Recruitment of β-arrestin into Neuronal Cilia Modulates Somatostatin Receptor Subtype 3 Ciliary Localization

2015 ◽  
pp. MCB.00765-15 ◽  
Author(s):  
Jill A. Green ◽  
Cullen L. Schmid ◽  
Elizabeth Bley ◽  
Paula C. Monsma ◽  
Anthony Brown ◽  
...  
Keyword(s):  
Primary Cilia ◽  
Somatostatin Receptor ◽  
Mammalian Brain ◽  
Receptor Subtype ◽  
Neuronal Cilia ◽  
Ciliary Function ◽  
Signaling Organelles ◽  
Subtype 3 ◽  
Ciliary Signaling ◽  
Ciliary Localization

Primary cilia are essential sensory and signaling organelles present on nearly every mammalian cell type. Defects in primary cilia underlie a class of human diseases collectively termed ciliopathies. Primary cilia are restricted subcellular compartments and specialized mechanisms coordinate localization of proteins to cilia. Moreover, trafficking of proteins into and out of cilia is required for proper ciliary function and this process is disrupted in ciliopathies. The somatostatin receptor subtype 3 (Sstr3) is selectively targeted to primary cilia on neurons in the mammalian brain and is implicated in learning and memory. Here, we show that Sstr3 localization to cilia is dynamic and decreases in response to somatostatin treatment. We further show that somatostatin treatment stimulates β-arrestin recruitment into Sstr3-positive cilia and this recruitment can be blocked by mutations in Sstr3 that impact agonist binding or phosphorylation. Importantly, somatostatin treatment fails to decrease Sstr3 ciliary localization in neurons lacking β-arrestin 2. Together, our results implicate β-arrestin in the modulation of Sstr3 ciliary localization and further suggest a role for β-arrestin in the mediation of Sstr3 ciliary signaling.

scholarly journals Ciliary neuropeptidergic signaling dynamically regulates excitatory synapses in postnatal neocortical pyramidal neurons

2020 ◽  
Author(s):  
Lauren Tereshko ◽  
Ya Gao ◽  
Brian A. Cary ◽  
Gina G. Turrigiano ◽  
Piali Sengupta
Keyword(s):  
Primary Cilia ◽  
Neuronal Development ◽  
Pyramidal Neurons ◽  
Somatostatin Receptor ◽  
Cognitive Disorders ◽  
Mammalian Brain ◽  
Excitatory Synapses ◽  
Ciliary Signaling ◽  
Neocortical Pyramidal Neurons

ABSTRACTPrimary cilia are compartmentalized sensory organelles present on the majority of neurons in the mammalian brain throughout adulthood. Recent evidence suggests that cilia regulate multiple aspects of neuronal development, including the maintenance of neuronal connectivity. However, whether ciliary signals can dynamically modulate postnatal circuit excitability is unknown. Here we show that acute cell-autonomous knockdown of ciliary signaling rapidly strengthens glutamatergic inputs onto cultured neocortical pyramidal neurons, and increases spontaneous firing. This increased excitability occurs without changes to passive neuronal properties or intrinsic excitability. Further, the neuropeptide receptor somatostatin receptor 3 (SSTR3) is localized nearly exclusively to pyramidal neuron cilia both in vivo and in culture, and pharmacological manipulation of SSTR3 signaling bidirectionally modulates excitatory synaptic inputs onto these neurons. Our results indicate that ciliary neuropeptidergic signaling dynamically modulates excitatory synapses, and suggest that defects in this regulation may underlie a subset of behavioral and cognitive disorders associated with ciliopathies.

scholarly journals HTR6 and SSTR3 targeting to primary cilia

2021 ◽  
Author(s):  
Pablo Barbeito ◽  
Francesc R. Garcia-Gonzalo
Keyword(s):  
Serotonin Receptor ◽  
Primary Cilia ◽  
Somatostatin Receptor ◽  
G Protein Coupled Receptors ◽  
Signal Transducers ◽  
Neuronal Cilia ◽  
Intracellular Loops ◽  
Oncologic Diseases ◽  
G Protein Coupled ◽  
Ciliary Localization

Primary cilia are hair-like projections of the cell membrane supported by an inner microtubule scaffold, the axoneme, which polymerizes out of a membrane-docked centriole at the ciliary base. By working as specialized signaling compartments, primary cilia provide an optimal environment for many G protein-coupled receptors (GPCRs) and their effectors to efficiently transmit their signals to the rest of the cell. For this to occur, however, all necessary receptors and signal transducers must first accumulate at the ciliary membrane. Serotonin receptor 6 (HTR6) and Somatostatin receptor 3 (SSTR3) are two GPCRs whose signaling in brain neuronal cilia affects cognition and is implicated in psychiatric, neurodegenerative, and oncologic diseases. Over a decade ago, the third intracellular loops (IC3s) of HTR6 and SSTR3 were shown to contain ciliary localization sequences (CLSs) that, when grafted onto non-ciliary GPCRs, could drive their ciliary accumulation. Nevertheless, these CLSs were dispensable for ciliary targeting of HTR6 and SSTR3, suggesting the presence of additional CLSs, which we have recently identified in their C-terminal tails. Herein, we review the discovery and mapping of these CLSs, as well as the state of the art regarding how these CLSs may orchestrate ciliary accumulation of these GPCRs by controlling when and where they interact with the ciliary entry and exit machinery via adaptors such as TULP3, RABL2 and the BBSome.

scholarly journals Ciliary neuropeptidergic signaling dynamically regulates excitatory synapses in postnatal neocortical pyramidal neurons

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Lauren Tereshko ◽  
Ya Gao ◽  
Brian A Cary ◽  
Gina G Turrigiano ◽  
Piali Sengupta
Keyword(s):  
Primary Cilia ◽  
Neuronal Development ◽  
Pyramidal Neurons ◽  
Somatostatin Receptor ◽  
Cognitive Disorders ◽  
Mammalian Brain ◽  
Excitatory Synapses ◽  
Ciliary Signaling ◽  
Neocortical Pyramidal Neurons

Primary cilia are compartmentalized sensory organelles present on the majority of neurons in the mammalian brain throughout adulthood. Recent evidence suggests that cilia regulate multiple aspects of neuronal development, including the maintenance of neuronal connectivity. However, whether ciliary signals can dynamically modulate postnatal circuit excitability is unknown. Here we show that acute cell-autonomous knockdown of ciliary signaling rapidly strengthens glutamatergic inputs onto cultured rat neocortical pyramidal neurons and increases spontaneous firing. This increased excitability occurs without changes to passive neuronal properties or intrinsic excitability. Further, the neuropeptide receptor somatostatin receptor 3 (SSTR3) is localized nearly exclusively to excitatory neuron cilia both in vivo and in culture, and pharmacological manipulation of SSTR3 signaling bidirectionally modulates excitatory synaptic inputs onto these neurons. Our results indicate that ciliary neuropeptidergic signaling dynamically modulates excitatory synapses and suggest that defects in this regulation may underlie a subset of behavioral and cognitive disorders associated with ciliopathies.

Somatostatin receptor subtype 3 mediates the inhibitory action of somatostatin on gastric smooth muscle cells

1995 ◽  
Vol 268 (5) ◽  
pp. G739-G748 ◽  
Author(s):  
Z. F. Gu ◽  
V. D. Corleto ◽  
S. A. Mantey ◽  
D. H. Coy ◽  
P. N. Maton ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Protease Inhibitors ◽  
Somatostatin Receptor ◽  
Muscle Cells ◽  
Receptor Subtype ◽  
Binding Studies ◽  
High Affinity ◽  
Gastric Smooth Muscle ◽  
Subtype 3

Previous functional studies show that somatostatin (SS) interacts with specific receptors to inhibit relaxation in gastric smooth muscle cells. There are no ligand binding studies, and it is unknown which of the five subtypes of SS receptors mediates the action. Dispersed gastric smooth muscle cells from guinea pig bound both 125I-labeled SS-14 and 125I-D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Cys-Nal-NH2 (where Nal indicates N-naphthylalanine) (cyclo-SS-8), a synthetic peptidase-resistant octapeptide SS analogue. SS-28 and SS-14, cyclo-SS-8, and SS analogue D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-ol [SMS-(201-995) (octreotide)] inhibited 125I-cyclo-SS-8 binding with relative potencies of SS-28 = cyclo-SS-8 = SMS-(201-995) (octreotide), and the binding was not affected by the addition of protease inhibitors. SS-14 caused inhibition only in the presence of protease inhibitors. Ligand analysis demonstrated a two-binding-site model. Analysis of the relationship between biological function and binding suggested the high-affinity sites mediated the relaxant action of SS. 5'-Guanylylimidodiphosphate [Gpp-(NH)p] inhibited binding by reducing the affinity of the high-affinity site. Six SS-8 analogues that distinguish SS subtypes showed that 125I-SS-14 bound to somatostatin receptor subtype 3 (SSTR3). The results demonstrated that gastric smooth muscle cells possess distinct receptors for SS of the SSTR3 subtype. Occupation of these sites inhibits relaxation in gastric smooth muscle cells. Modulation between the high- and low- affinity binding states of SSTR3 is at least partially mediated by activation of guanine nucleotide regulatory proteins.

Agonist-Mediated Endocytosis of Rat Somatostatin Receptor Subtype 3 Involves β-Arrestin and Clathrin Coated Vesicles

2001 ◽  
Vol 13 (3) ◽  
pp. 279-287 ◽  
Author(s):  
O. J. Kreuzer ◽  
B. Krisch ◽  
O. Déry ◽  
N. W. Bunnett ◽  
W. Meyerhof
Keyword(s):  
Somatostatin Receptor ◽  
Coated Vesicles ◽  
Receptor Subtype ◽  
Subtype 3

scholarly journals Htr6 and Sstr3 ciliary targeting relies on both IC3 loops and C-terminal tails

2020 ◽  
Author(s):  
Pablo Barbeito ◽  
Yuki Tachibana ◽  
Raquel Martin-Morales ◽  
Paula Moreno ◽  
Kirk Mykytyn ◽  
...  
Keyword(s):  
Serotonin Receptor ◽  
Primary Cilia ◽  
Molecular Mechanisms ◽  
Somatostatin Receptor ◽  
Membrane Protrusions ◽  
The Individual ◽  
Intracellular Loops ◽  
G Protein Coupled ◽  
Shed Light ◽  
Ciliary Localization

ABSTRACTG protein-coupled receptors (GPCRs) are the most common pharmacological target in clinical practice. To perform their signaling functions, many GPCRs must accumulate at primary cilia, microtubule-based plasma membrane protrusions that work as cellular antennae. Despite their great importance, the molecular mechanisms underlying GPCR ciliary targeting remain poorly understood. Serotonin receptor 6 (Htr6) and somatostatin receptor 3 (Sstr3) are two brain-enriched ciliary GPCRs controlling cognition and involved in multiple pathologies such as Alzheimer’s disease and cancer. We previously showed that the third intracellular loops (IC3s) of Htr6 and Sstr3 contain ciliary targeting sequences (CTSs) that are sufficient to confer ciliary localization to non-ciliary GPCRs. However, these CTSs are dispensable for the ciliary targeting of Htr6 and Sstr3 themselves, suggesting these GPCRs have additional CTSs. Herein, we show that the C-terminal tails of Htr6 and Sstr3 also contain CTSs, which act redundantly with those in the IC3s. Accordingly, simultaneous disruption of CTS1 (IC3) and CTS2 (C-terminal tail) abolishes ciliary targeting of both receptors. Mapping the individual residues required for Htr6 ciliary targeting reveals RKQ and LPG motifs critical for CTS1 and CTS2 function, respectively. In Sstr3, CTS1 function relies on the tandem AP[AS]CQ motifs and a subsequent arginine-rich stretch, whereas CTS2 operation requires the juxtamembrane residues. Furthermore, we shed light on the mechanisms of action of Htr6 CTSs by showing how they regulate binding to Tulp3 and Rabl2, two adapters needed for ciliary GPCR targeting.

scholarly journals A Somatostatin Receptor Subtype-3 (SST3) Peptide Agonist Shows Antitumor Effects in Experimental Models of Nonfunctioning Pituitary Tumors

2019 ◽  
Vol 26 (4) ◽  
pp. 957-969 ◽  
Author(s):  
Mari C. Vázquez-Borrego ◽  
Vandana Gupta ◽  
Alejandro Ibáñez-Costa ◽  
Manuel D. Gahete ◽  
Eva Venegas-Moreno ◽  
...  
Keyword(s):  
Somatostatin Receptor ◽  
Pituitary Tumors ◽  
Experimental Models ◽  
Receptor Subtype ◽  
Antitumor Effects ◽  
Peptide Agonist ◽  
Subtype 3
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