Stress-Induced Redistribution of Corticotropin-Releasing Factor Receptor Subtypes in the Dorsal Raphe Nucleus

Waselus, Maria; Nazzaro, Cristiano; Valentino, Rita J.; Bockstaele, Elisabeth J. Van

doi:10.1016/j.biopsych.2009.02.014

Cited by 106 publications

(147 citation statements)

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“…CRF 2α R is localized intracellularly in neurons of the rat dorsal raphe nucleus and that exposure to acute (22) and repeated stress (23) increases its presence in the plasma membrane. CRF 2α R overexpressed in human embryonic kidney (HEK293T) cells is associated with the endoplasmic reticulum (ER) (24).…”

mentioning

confidence: 99%

CRF binding protein facilitates the presence of CRF type 2α receptor on the cell surface

Slater

Cerda

Pereira

et al. 2016

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

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Corticotropin releasing factor binding protein (CRF-BP) was originally recognized as CRF sequestering protein. However, its differential subcellular localization in different brain nuclei suggests that CRF-BP may have additional functions. There is evidence that CRF-BP potentiates CRF and urocortin 1 actions through CRF type 2 receptors (CRF 2 R). CRF 2 R is a G protein-coupled receptor (GPCR) that is found mainly intracellularly as most GPCRs. The access of GPCRs to the cell surface is tightly regulated by escort proteins. We hypothesized that CRF-BP binds to CRF 2 R, exerting an escort protein role. We analyzed the colocalization of CRF-BP and CRF 2 R in cultured rat mesencephalic neurons, and the localization and interaction of heterologous expressed CRF-BP and CRF 2α R in yeast, human embryonic kidney 293, and rat pheochromocytoma 12 cells. Our results showed that CRF-BP and CRF 2 R naturally colocalize in the neurites of cultured mesencephalic neurons. Heterologous expression of each protein showed that CRF-BP was localized mainly in secretory granules and CRF 2α R in the endoplasmic reticulum. In contrast, CRF-BP and CRF 2α R colocalized when both proteins are coexpressed. Here we show that CRF-BP physically interacts with the CRF 2α R but not the CRF 2β R isoform, increasing CRF 2α R on the cell surface. Thus, CRF-BP emerges as a GPCR escort protein increasing the understanding of GPCR trafficking.T he corticotropin releasing factor (CRF) system plays a key role in the response and adaptation to stressful stimuli (1, 2) and in the interaction between stress and addiction (3). The CRF system acts on the hypothalamic-pituitary-adrenal axis (4, 5) and in different brain regions (1, 6). The CRF system includes four peptides, CRF type 1 (CRF 1 R) and type 2 (CRF 2 R), G protein-coupled receptors (GPCRs) (6-8), and CRF binding protein (CRF-BP) (9). CRF-BP was described as a circulating polypeptide in pregnant women (10, 11). CRF-BP binds CRF and urocortin with high affinity (12). Different functions have been proposed for CRF-BP (13). On one hand, CRF-BP exerts an inhibitory role by sequestering CRF peptide (9, 14-16). On other hand, a facilitatory role of CRF-BP on CRF-dependent neuronal plasticity depending on CRF 2 R in the rat ventral tegmental area (VTA) has been described (17, 18). Recently, it has been shown that CRF-BP and CRF 2 R are important for ethanol binge drinking behavior (19). The anatomical evidence showing that CRF-BP has different subcellular distribution depending on the neuronal context (20) further supports several roles for CRF-BP.Three isoforms of CRF 2 R have been reported, the α isoform being the most expressed in the brain (21). CRF 2α R is localized intracellularly in neurons of the rat dorsal raphe nucleus and that exposure to acute (22) and repeated stress (23) increases its presence in the plasma membrane. CRF 2α R overexpressed in human embryonic kidney (HEK293T) cells is associated with the endoplasmic reticulum (ER) (24). Schulz et al. (25) showed that CRF 2α R is retained in...

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mentioning

confidence: 99%

CRF binding protein facilitates the presence of CRF type 2α receptor on the cell surface

Slater

Cerda

Pereira

et al. 2016

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

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“…For example, prior swim stress induces the recruitment of CRF 2 receptors from the cytoplasm to the plasma membrane and tends to promote CRF 1 internalization (Waselus et al, 2009). This qualitatively changes the response to CRF from a CRF 1 -mediated inhibition to a CRF 2 -mediated excitation.…”

Section: Social Stress Experience Alters the Cognitive Impact Of Intrmentioning

confidence: 99%

“…For example, following swim stress CRF 2 is recruited to the plasma membrane and CRF 1 becomes internalized, resulting in a qualitative shift in neuronal responses to CRF from inhibition to excitation (Waselus et al, 2009). Repeated social stress produces a similar redistribution of CRF receptors and shift in neuronal response to CRF selectively in a subpopulation of rats that resist defeat (Wood et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Corticotropin-releasing Factor in the Rat Dorsal Raphe Nucleus Promotes Different Forms of Behavioral Flexibility Depending on Social Stress History

Snyder

Hill-Smith

Lucki

et al. 2015

Neuropsychopharmacol

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The stress-related neuropeptide, corticotropin-releasing factor (CRF) regulates the dorsal raphe nucleus-serotonin (DRN-5-HT) system during stress and this may underlie affective and cognitive dysfunctions that characterize stress-related psychiatric disorders. CRF acts on both CRF 1 and CRF 2 receptor subtypes in the DRN that exert opposing inhibitory and excitatory effects on DRN-5-HT neuronal activity and 5-HT forebrain release, respectively. The current study first assessed the cognitive effects of intra-DRN microinfusion of CRF or the selective CRF 2 agonist, urocortin II in stress-naive rats on performance of an operant strategy set-shifting task that is mediated by the medial prefrontal cortex (mPFC). CRF (30 ng) facilitated strategy set-shifting performance, whereas higher doses of CRF and urocortin II that would interact with CRF 2 were without effect, consistent with a CRF 1 -mediated action. This dose decreased 5-HT extracellular levels in the mPFC, further supporting a role for CRF 1 . The effects of CRF were then assessed in rats exposed to repeated social stress using the resident-intruder model. Repeated social stress shifted the CRF effect from facilitation of strategy set shifting to facilitation of reversal learning and this was most prominent in a subpopulation of rats that resist defeat. Notably, in this subpopulation of rats 5-HT neuronal responses to CRF have been demonstrated to shift from CRF 1 -mediated inhibition to CRF 2 -mediated excitation. Because 5-HT facilitates reversal learning, the present results suggest that stress-induced changes in the cellular effects of CRF in the DRN translate to changes in cognitive effects of CRF. Together, the results underscore the potential for stress history to shift cognitive processing through changes in CRF neurotransmission in the DRN and the association of this effect with coping strategy.

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“…Interestingly, CRF-induced 5-HT release in the amygdala appears to be dependent on CRF2 receptor activation in the dRN [131,133], and CRF2 receptors are known to increase 5-HT neuronal firing rates in the dRN [141]. Importantly, increased neuronal surface expression of CRF2 receptors occurs in the dRN as a result of stress [142], and increased expression of CRF2 receptors in the dRN has been observed in rat models of high anxiety [11,128,137,143]. Furthermore, CRF2 receptor antagonists infused directly into the dRN reduce heightened anxiety-like behavior in rat models of amphetamine withdrawal or early life stress [12,128].…”

Section: Monoaminergic Neurotransmission In the Amygdala: Relation Tomentioning

confidence: 99%

The Role of the Amygdala in Anxiety Disorders

Forster¹,

Novick²,

Scholl³

et al. 2012

The Amygdala - A Discrete Multitasking Manager

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Stress-Induced Redistribution of Corticotropin-Releasing Factor Receptor Subtypes in the Dorsal Raphe Nucleus

Cited by 106 publications

References 30 publications

CRF binding protein facilitates the presence of CRF type 2α receptor on the cell surface

CRF binding protein facilitates the presence of CRF type 2α receptor on the cell surface

Corticotropin-releasing Factor in the Rat Dorsal Raphe Nucleus Promotes Different Forms of Behavioral Flexibility Depending on Social Stress History

The Role of the Amygdala in Anxiety Disorders

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