scholarly journals β-arrestin-dependent ERK signaling positively correlates with reduced anxiety-like and conditioned fear-related behavior in mice

2019 ◽  
Author(s):  
Mee Jung Ko ◽  
Terrance Chiang ◽  
Arbaaz A. Mukadam ◽  
Grace E. Mulia ◽  
Anna M. Gutridge ◽  
...  
Keyword(s):  
G Protein ◽  
Dorsal Hippocampus ◽  
Conditioned Fear ◽  
G Protein Coupled Receptors ◽  
Erk Signaling ◽  
Extracellular Signal ◽  
Δ Opioid Receptor ◽  
Fear And Anxiety ◽  
G Protein Coupled ◽  
The Brain

AbstractExposure to anxiety- or fear-invoking stimuli initiates a convergence of executive actions orchestrated by multiple proteins and neurotransmitters across the brain. Dozens of G protein-coupled receptors (GPCRs) have been linked to regulation of fear and anxiety. GPCR signaling involves canonical G protein pathways but may also engage downstream kinases and effectors through β-arrestin scaffolds. Here, we investigate whether β-arrestin signaling can regulate anxiety-like and fear-related behavior. Using the δ-opioid receptor (δOR) as a model GPCR, we found that β-arrestin 2-dependent activation of extracellular signal–regulated kinases (ERK1/2) in the dorsal hippocampus and the amygdala are critical for δOR agonist-induced anxiolytic-like effects. In contrast, G protein-mediated δOR signaling was associated with decreased ERK1/2 activity and increased fear-related behavior. Our results also indicate unique contributions for β-arrestin isoforms in modulation of anxiety-like and fear-related behavior. Overall, our findings highlight the significance of non-canonical β-arrestin signaling in the regulation of emotions.One sentence summaryUsing pharmacological and genetic strategies, we reveal the importance of non-canonical β-arrestin-mediated G protein-coupled receptor signaling in anxiety-like behaviors.

scholarly journals β-Arrestin–dependent ERK signaling reduces anxiety-like and conditioned fear–related behaviors in mice

2021 ◽  
Vol 14 (694) ◽  
pp. eaba0245
Author(s):  
Mee Jung Ko ◽  
Terrance Chiang ◽  
Arbaaz A. Mukadam ◽  
Grace E. Mulia ◽  
Anna M. Gutridge ◽  
...  
Keyword(s):  
G Protein ◽  
Dorsal Hippocampus ◽  
Conditioned Fear ◽  
Dorsal Striatum ◽  
Erk Signaling ◽  
Gpcr Signaling ◽  
Biased Signaling ◽  
Complex Picture ◽  
Δ Opioid Receptor ◽  
Fear And Anxiety

G protein–coupled receptors (GPCRs) are implicated in the regulation of fear and anxiety. GPCR signaling involves canonical G protein pathways but can also engage downstream kinases and effectors through scaffolding interactions mediated by β-arrestin. Here, we investigated whether β-arrestin signaling regulates anxiety-like and fear-related behavior in mice in response to activation of the GPCR δ-opioid receptor (δOR or DOR). Administration of β-arrestin–biased δOR agonists to male C57BL/6 mice revealed β-arrestin 2–dependent activation of extracellular signal–regulated kinases 1 and 2 (ERK1/2) in the dorsal hippocampus and amygdala and β-arrestin 1–dependent activation of ERK1/2 in the nucleus accumbens. In mice, β-arrestin–biased agonist treatment was associated with reduced anxiety-like and fear-related behaviors, with some overlapping and isoform-specific input. In contrast, applying a G protein–biased δOR agonist decreased ERK1/2 activity in all three regions as well as the dorsal striatum and was associated with increased fear-related behavior without effects on baseline anxiety. Our results indicate a complex picture of δOR neuromodulation in which β-arrestin 1– and 2–dependent ERK signaling in specific brain subregions suppresses behaviors associated with anxiety and fear and opposes the effects of G protein–biased signaling. Overall, our findings highlight the importance of noncanonical β-arrestin–dependent GPCR signaling in the regulation of these interrelated emotions.

scholarly journals Effect of 5-hydroxytryptamine Receptor in the Lower Esophageal Sphincter Regulation Mechanism

2020 ◽  
Vol 3 (6) ◽  
Author(s):  
Hefei Li ◽  
Junfeng Liu ◽  
Xixuan Zhang ◽  
Zhiwei Lai ◽  
Zhen Gao ◽  
...  
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Regulation Mechanism ◽  
Visceral Sensitivity ◽  
Gastrointestinal Dysfunction ◽  
Secretion Regulation ◽  
The Central Nervous System ◽  
Esophageal Sphincter ◽  
G Protein Coupled ◽  
The Brain

As a neurotransmitter and avascular active substance, the 5-hydroxytryptamine (5-HT, serotonin) is widely distributed in the central nervous system and surrounding tissues. The 5-HT can play its role by acting on its corresponding 5-HT receptor. Nowadays, the 5-HT receptor can be classified into seven, according to different signal transduction method of receptors, the 5-HT3 receptor belongs to the ligand-gated ion channels, while other six 5-HT receptors are involved into the G protein-coupled receptors and play the biological role by binding to specific G protein-coupled receptors (GPCRs) on the surface of the cell membrane. The 5-HT plays an important role in the brain-gut information transmission and studies showed that the physiological stimulations like having meals, and pathological stimulations like ischemia and stress could promote the release of the 5-HT. In the gastrointestinal tract, the 5-HT is closely related to gastrointestinal sensitivity, gastrointestinal movement and secretion regulation, as well as many gastrointestinal dysfunction disorders, such as gastrointestinal power and visceral sensitivity abnormality and abnormalities of brain-gut axis.

Complementary roles of mouse lipocalins in chemical communication and immunity

2014 ◽  
Vol 42 (4) ◽  
pp. 893-898 ◽  
Author(s):  
Romana Stopková ◽  
Barbora Dudková ◽  
Petra Hájková ◽  
Pavel Stopka
Keyword(s):  
Oral Cavity ◽  
G Protein ◽  
Primary Site ◽  
G Protein Coupled Receptors ◽  
Main Route ◽  
Evolutionary Forces ◽  
Biochemical Pathways ◽  
G Protein Coupled ◽  
The Brain ◽  
Exogenous Substances

A primary site of infection in mammals is the nostrils, representing the gate to the brain through olfactory and vomeronasal epithelia, eyes as a direct route to the brain via the optical nerve, and oral cavity representing the main route to the digestive tract. Similarly, pheromones, odorants and tastants enter animal bodies the same way. Therefore similar evolutionary forces might have shaped the evolution of systems for recognition of pathogens and chemical signals. This might have resulted in sharing various proteins among systems of recognition and filtering to decrease potential costs of evolving and utilizing unique biochemical pathways. This has been documented previously in, for example, multipurpose and widely distributed GPCRs (G-protein-coupled receptors). The aim of the present review is to explore potential functional overlaps or complementary functions of lipocalins in the system of perception of exogenous substances to reconstruct the evolutionary forces that might have shaped their synergistic functions.

scholarly journals Noncanonical scaffolding of Gαi and β-arrestin by G protein-coupled receptors

2019 ◽  
Author(s):  
Jeffrey S. Smith ◽  
Thomas F. Pack ◽  
Asuka Inoue ◽  
Claudia Lee ◽  
Xinyu Xiong ◽  
...  
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Environmental Signals ◽  
Extracellular Signal Regulated Kinase ◽  
Intracellular Signals ◽  
Extracellular Signal ◽  
Extracellular Stimuli ◽  
Protein Isoform ◽  
Sense And Respond ◽  
G Protein Coupled

SummaryG-protein-coupled receptors (GPCRs) enable cells to sense and respond appropriately to hormonal and environmental signals, and are a target of ~30% of all FDA-approved medications. Canonically, each GPCR couples to distinct Gα proteins, such as Gαs, Gαi, Gαq or Gα12/13, as well as β-arrestins. These transducer proteins translate and integrate extracellular stimuli sensed by GPCRs into intracellular signals through what are broadly considered separable signalling pathways. However, the ability of Gα proteins to directly interact with β-arrestins to integrate signalling has not previously been appreciated. Here we show a novel interaction between Gαi protein family members and β-arrestin. Gαi:β-arrestin complexes were formed by all GPCRs tested, regardless of their canonical G protein isoform coupling, and could bind both GPCRs as well as the extracellular signal-regulated kinase (ERK). This novel paradigm of Gαi:β-arrestin scaffolds enhances our understanding of GPCR signalling.

scholarly journals A new family of orphan G protein-coupled receptors predominantly expressed in the brain 1

FEBS Letters ◽  
1998 ◽  
Vol 424 (3) ◽  
pp. 193-196 ◽  
Author(s):  
Olivier Valdenaire ◽  
Thomas Giller ◽  
Volker Breu ◽  
Ali Ardati ◽  
Anja Schweizer ◽  
...  
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
New Family ◽  
G Protein Coupled ◽  
The Brain
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