Tyrosine receptor kinase B receptor activation reverses the impairing effects of acute nicotine on contextual fear extinction

The G protein-coupled receptor kinase (GRK2) belongs to a family of protein kinases that phosphorylates agonist-activated G protein-coupled receptors, leading to G protein-receptor uncoupling and termination of G protein signaling. GRK2 also contains a regulator of G protein signaling homology (RH) domain, which selectively interacts with α-subunits of the Gq/11 family that are released during G protein-coupled receptor activation. We have previously reported that kinase activity of GRK2 up-regulates activity of the epithelial sodium channel (ENaC) in a Na+ absorptive epithelium by blocking Nedd4-2-dependent inhibition of ENaC. In the present study, we report that GRK2 also regulates ENaC by a mechanism that does not depend on its kinase activity. We show that a wild-type GRK2 (wtGRK2) and a kinase-dead GRK2 mutant (K220RGRK2), but not a GRK2 mutant that lacks the C-terminal RH domain (ΔRH-GRK2) or a GRK2 mutant that cannot interact with Gαq/11/14 (D110AGRK2), increase activity of ENaC. GRK2 up-regulates the basal activity of the channel as a consequence of its RH domain binding the α-subunits of Gq/11. We further found that expression of constitutively active Gαq/11 mutants significantly inhibits activity of ENaC. Conversely, co-expression of siRNA against Gαq/11 increases ENaC activity. The effect of Gαq on ENaC activity is not due to change in ENaC membrane expression and is independent of Nedd4-2. These findings reveal a novel mechanism by which GRK2 and Gq/11 α-subunits regulate the activity ENaC.

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Contextual Fear Extinction and Re-Extinction in Carioca High- and Low-Conditioned Freezing Rats

World Journal of Neuroscience ◽

10.4236/wjns.2014.43028 ◽

2014 ◽

Vol 04 (03) ◽

pp. 247-252 ◽

Cited By ~ 3

Author(s):

Vitor de Castro Gomes ◽

Laura Andrea León ◽

Daniel Mograbi ◽

Fernando Cardenas ◽

Jesus Landeira-Fernandez

Keyword(s):

Fear Extinction ◽

Contextual Fear ◽

Conditioned Freezing

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Fibrinogen-cellular prion protein complex formation on astrocytes

Journal of Neurophysiology ◽

10.1152/jn.00224.2020 ◽

2020 ◽

Vol 124 (2) ◽

pp. 536-543 ◽

Cited By ~ 2

Author(s):

Mariam Charkviani ◽

Nino Muradashvili ◽

Nurul Sulimai ◽

David Lominadze

Keyword(s):

Prion Protein ◽

Cellular Prion Protein ◽

No Production ◽

Oxygen Species ◽

Receptor Kinase ◽

Astrocyte Activation ◽

Triggering Mechanism ◽

Protein Complex Formation ◽

Tyrosine Receptor Kinase ◽

First Time

For the first time we showed that fibrinogen (Fg) can associate with cellular prion protein (PrPC) on the surface of cultured mouse brain astrocytes. At high levels, Fg causes upregulation of astrocyte PrPC and astrocyte activation accompanied with overexpression of tyrosine receptor kinase B (TrkB), which results in nitric oxide (NO) production and generation of reactive oxygen species (ROS). Fg/PrPC interaction can be a triggering mechanism for TrkB-NO-ROS axis activation and the resultant astrocyte-mediated neurodegeneration.

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Cholinergic neuronal lesions in the medial septum and vertical limb of the diagonal bands of Broca induce contextual fear memory generalization and impair acquisition of fear extinction

Hippocampus ◽

10.1002/hipo.22553 ◽

2015 ◽

Vol 26 (6) ◽

pp. 718-726 ◽

Cited By ~ 21

Author(s):

Dayan Knox ◽

Samantha M. Keller

Keyword(s):

Fear Memory ◽

Medial Septum ◽

Fear Extinction ◽

Contextual Fear ◽

Contextual Fear Memory

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Translational Research from Animals to Humans

10.1093/med/9780190215422.003.0017 ◽

2016 ◽

Author(s):

Shigeru Morinobu ◽

Shigeto Yamamoto ◽

Manabu Fuchikami

Keyword(s):

Animal Model ◽

Fear Conditioning ◽

Fear Extinction ◽

Contextual Fear Conditioning ◽

Behavioral Characteristics ◽

Post Traumatic Stress ◽

Contextual Fear ◽

Glycine Transporter 1 ◽

Post Traumatic ◽

Prolonged Stress

To elucidate the pathophysiology of post-traumatic stress disorder (PTSD), the establishment of an appropriate animal model is necessary. In a series of studies, the authors validated single prolonged stress (SPS) as a model for PTSD. SPS-treated rats mimic the pathophysiological abnormalities and behavioral characteristics of PTSD, such as enhanced anxiety-like behavior, glucocorticoid negative feedback, and analgesia. In addition, the authors demonstrated enhanced freezing in response to contextual fear conditioning, and impaired extinction of fear memory, which was alleviated by D-cycloserine (DCS). In parallel, there was a decrease in extracellular glycine mediated by an increase in glycine transporter 1 in the hippocampus of SPS-treated rats after fear conditioning, which suggested that activation of N-methyl-D-asparate receptor by DCS during fear extinction training might alleviate the impaired fear extinction. This chapter summarizes PTSD-like symptoms in SPS and evaluates the validity of SPS as an animal model of PTSD.

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