scholarly journals Single-Cell Transcriptomic Evidence for Dense Intracortical Neuropeptide Networks

2019 ◽  
Author(s):  
Stephen J Smith ◽  
Uygar Sümbül ◽  
Lucas Graybuck ◽  
Forrest Collman ◽  
Sharmishtaa Seshamani ◽  
...  
Keyword(s):  
Single Cell ◽  
G Protein ◽  
Cortical Neurons ◽  
Expression Patterns ◽  
List Type ◽  
Neuron Type ◽  
Sequencing Data ◽  
G Protein Coupled Receptor ◽  
Neocortical Neurons ◽  
G Protein Coupled

SummarySeeking new insights into the homeostasis, modulation and plasticity of cortical synaptic networks, we have analyzed results from a single-cell RNA-seq study of 22,439 mouse neocortical neurons. Our analysis exposes transcriptomic evidence for dozens of molecularly distinct neuropeptidergic modulatory networks that directly interconnect all cortical neurons. This evidence begins with a discovery that transcripts of one or more neuropeptide precursor (NPP) and one or more neuropeptide-selective G-protein-coupled receptor (NP-GPCR) genes are highly abundant in all, or very nearly all, cortical neurons. Individual neurons express diverse subsets of NP signaling genes from palettes encoding 18 NPPs and 29 NP-GPCRs. These 47 genes comprise 37 cognate NPP/NP-GPCR pairs, implying the likelihood of local neuropeptide signaling. Here we use neuron-type-specific patterns of NP gene expression to offer specific, testable predictions regarding 37 peptidergic neuromodulatory networks that may play prominent roles in cortical homeostasis and plasticity.ImpactSingle-cell mRNA sequencing data from mouse neocortex expose evidence for peptidergic neuromodulatory networks that locally interconnect every cortical neuronData HighlightsAt least 97% of mouse neocortical neurons express one or more of 18 neuropeptide precursor proteins (NPP) genes at very high levelsAt least 98% of cortical neurons express one or more of 29 neuropeptide-selective G-protein-coupled receptor (NP-GPCR) genes cognate to the 18 highly expressed NPP genesNeocortical expression of these 18 NPP and 29 NP-GPCR genes is highly neuron-type-specific and their expression patterns differentiate transcriptomic neuron types with exceptional powerNeuron-type taxonomy and type-specific expression of 37 cognate NPP / NP-GPCR gene pairs generate testable predictions of at least 37 local intracortical neuromodulation networks

scholarly journals Single-cell transcriptomic evidence for dense intracortical neuropeptide networks

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Stephen J Smith ◽  
Uygar Sümbül ◽  
Lucas T Graybuck ◽  
Forrest Collman ◽  
Sharmishtaa Seshamani ◽  
...  
Keyword(s):  
Gene Expression ◽  
Single Cell ◽  
G Protein ◽  
Cortical Neurons ◽  
Neuron Type ◽  
Rna Seq ◽  
G Protein Coupled Receptor ◽  
Neocortical Neurons ◽  
Np Gene ◽  
G Protein Coupled

Seeking new insights into the homeostasis, modulation and plasticity of cortical synaptic networks, we have analyzed results from a single-cell RNA-seq study of 22,439 mouse neocortical neurons. Our analysis exposes transcriptomic evidence for dozens of molecularly distinct neuropeptidergic modulatory networks that directly interconnect all cortical neurons. This evidence begins with a discovery that transcripts of one or more neuropeptide precursor (NPP) and one or more neuropeptide-selective G-protein-coupled receptor (NP-GPCR) genes are highly abundant in all, or very nearly all, cortical neurons. Individual neurons express diverse subsets of NP signaling genes from palettes encoding 18 NPPs and 29 NP-GPCRs. These 47 genes comprise 37 cognate NPP/NP-GPCR pairs, implying the likelihood of local neuropeptide signaling. Here, we use neuron-type-specific patterns of NP gene expression to offer specific, testable predictions regarding 37 peptidergic neuromodulatory networks that may play prominent roles in cortical homeostasis and plasticity.

scholarly journals The Vertical and Horizontal Pathways in the Monkey Retina Are Modulated by Typical and Atypical Cannabinoid Receptors

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3160
Author(s):  
Joseph Bouskila ◽  
Maxime Bleau ◽  
Catarina Micaelo-Fernandes ◽  
Jean-François Bouchard ◽  
Maurice Ptito
Keyword(s):  
G Protein ◽  
Visual Information ◽  
Cannabinoid Receptors ◽  
Transient Receptor Potential ◽  
Expression Patterns ◽  
Retinal Function ◽  
Age Related Macular Degeneration ◽  
Transient Receptor Potential Vanilloid ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled

The endocannabinoid (eCB) system has been found in all visual parts of the central ner-vous system and plays a role in the processing of visual information in many species, including monkeys and humans. Using anatomical methods, cannabinoid receptors are present in the monkey retina, particularly in the vertical glutamatergic pathway, and also in the horizontal GABAergic pathway. Modulating the eCB system regulates normal retinal function as demonstrated by electrophysiological recordings. The characterization of the expression patterns of all types of cannabinoid receptors in the retina is progressing, and further research is needed to elucidate their exact role in processing visual information. Typical cannabinoid receptors include G-protein coupled receptor CB1R and CB2R, and atypical cannabinoid receptors include the G-protein coupled receptor 55 (GPR55) and the ion channel transient receptor potential vanilloid 1 (TRPV1). This review focuses on the expression and localization studies carried out in monkeys, but some data on other animal species and humans will also be reported. Furthermore, the role of the endogenous cannabinoid receptors in retinal function will also be presented using intraocular injections of known modulators (agonists and antagonists) on electroretinographic patterns in monkeys. The effects of the natural bioactive lipid lysophosphatidylglucoside and synthetic FAAH inhibitor URB597 on retinal function, will also be described. Finally, the potential of typical and atypical cannabinoid receptor acti-vity regulation in retinal diseases, such as age-related macular degeneration, diabetic retinopathy, glaucoma, and retinitis pigmentosa will be briefly explored.

Developmental and adult expression patterns of the G-protein-coupled receptor GPR88 in the rat: Establishment of a dual nuclear-cytoplasmic localization

2016 ◽  
Vol 524 (14) ◽  
pp. 2776-2802 ◽  
Author(s):  
Renaud Massart ◽  
Virginie Mignon ◽  
Jennifer Stanic ◽  
Paola Munoz-Tello ◽  
Jerôme A.J. Becker ◽  
...  
Keyword(s):  
G Protein ◽  
Expression Patterns ◽  
Cytoplasmic Localization ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled

scholarly journals In vitro profiling of orphan G protein coupled receptor (GPCR) constitutive activity

2021 ◽  
Author(s):  
Lyndsay R. Watkins ◽  
Cesare Orlandi
Keyword(s):  
G Protein ◽  
Luciferase Reporter ◽  
List Type ◽  
Constitutive Activity ◽  
Protein Signaling ◽  
G Protein Coupled Receptor ◽  
Orphan Receptors ◽  
Gpcr Family ◽  
Orphan Gpcrs ◽  
G Protein Coupled

AbstractBackground and PurposeMembers of the G protein coupled receptor (GPCR) family are targeted by a significant fraction of the available FDA-approved drugs. However, the physiological role and pharmacological properties of many GPCRs remain unknown, representing untapped potential in drug design. Of particular interest are ~100 less-studied GPCRs known as orphans because their endogenous ligands are unknown. Intriguingly, disease-causing mutations identified in patients, together with animal studies, have demonstrated that many orphan receptors play crucial physiological roles, and thus, represent attractive drug targets.Experimental ApproachThe majority of deorphanized GPCRs demonstrate coupling to Gi/o, however a limited number of techniques allow the detection of intrinsically small constitutive activity associated with Gi/o protein activation which represents a significant barrier in our ability to study orphan GPCR signaling. Using luciferase reporter assays, we effectively detected constitutive Gs, Gq, and G12/13 protein signaling by unliganded receptors, and introducing various G protein chimeras, we provide a novel, highly-sensitive tool capable of identifying Gi/o coupling in unliganded orphan GPCRs.Key ResultsUsing this approach, we measured the constitutive activity of the entire class C GPCR family that includes 8 orphan receptors, and a subset of 20 prototypical class A GPCR members, including 11 orphans. Excitingly, this approach illuminated the G protein coupling profile of 8 orphan GPCRs (GPR22, GPR137b, GPR88, GPR156, GPR158, GPR179, GPRC5D, and GPRC6A) previously linked to pathophysiological processes.Conclusion and ImplicationsWe provide a new platform that could be utilized in ongoing studies in orphan receptor signaling and deorphanization efforts.What is already knownA large group of understudied orphan GPCRs controls a variety of physiological process.What this study addsA new strategy to identify G protein signaling associated with orphan GPCRs.Identification of Gi/o coupling for 8 orphan GPCRs.What is the clinical significanceMany orphan GPCRs are associated with pathological conditions and represent promising druggable targets.

scholarly journals Dissociation of the intramolecularly cleaved N- and C-terminal fragments of the adhesion G protein-coupled receptor GPR133 (ADGRD1) increases canonical signaling

2020 ◽  
Author(s):  
Joshua D. Frenster ◽  
Gabriele Stephan ◽  
Niklas Ravn-Boess ◽  
Devin Bready ◽  
Jordan Wilcox ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
G Protein ◽  
Receptor Activation ◽  
List Type ◽  
G Protein Coupled Receptor ◽  
Major Mechanism ◽  
N Terminus ◽  
Adhesion Gpcr ◽  
G Protein Coupled

SUMMARYGPR133 (ADGRD1), an adhesion G protein-coupled receptor (GPCR), is necessary for growth of glioblastoma (GBM), a brain malignancy. The extracellular N-terminus of GPR133 is thought to be autoproteolytically cleaved into an N-terminal and a C-terminal fragment (NTF and CTF). Nevertheless, the role of this cleavage in receptor activation remains unclear. Here, we show that the wild-type (WT) receptor is cleaved after protein synthesis and generates significantly more canonical signaling than an uncleavable point mutant (H543R) in patient-derived GBM cultures and HEK293T cells. However, the resulting NTF and CTF remain non-covalently bound until the receptor is trafficked to the plasma membrane, where we find NTF-CTF dissociation. Using a fusion of the hPAR1 receptor N-terminus and the CTF of GPR133, we demonstrate that thrombin-induced cleavage and shedding of the hPAR1 NTF increases receptor signaling. This study supports a model where dissociation of the NTF at the plasma membrane promotes GPR133 activation.Highlights-GPR133 is intramolecularly cleaved in patient-derived GBM cultures-Cleaved GPR133 signals at higher efficacy than the uncleavable GPR133 H543R mutant-The N- and C-terminal fragments (NTF and CTF) of GPR133 dissociate at the plasma membrane-Acute thrombin-induced cleavage of the human PAR1 NTF from the GPR133 CTF increases signalingeTOC BlurbFrenster et al. demonstrate intramolecular cleavage of the adhesion GPCR GPR133 in glioblastoma and HEK293T cells. The resulting N- and C-terminal fragments dissociate at the plasma membrane to increase canonical signaling. The findings suggest dissociation of GPR133’s N-terminus at the plasma membrane represents a major mechanism of receptor activation.

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