Molecular Mechanisms of Corticotropin-Releasing Factor Receptor-Induced Calcium Signaling

Gutknecht, Eric; Linden, Ilse Van der; Kolen, Kristof Van; Verhoeven, Kim F. C.; Vauquelin, Georges; Dautzenberg, Frank M.

doi:10.1124/mol.108.050427

Cited by 41 publications

(43 citation statements)

References 39 publications

(53 reference statements)

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“…Consistent with previous results from other groups (10, 11), a bellshaped concentration-response curve was recorded for the CRF 1 R. This unusual curve results from the fact that the receptor couples to G s at low agonist occupancy but also to G i at high occupancy (10,11). Coupling to G i was confirmed by blunting the concentration-response curve by pertussis toxin pretreatment (data not shown).…”

Section: The Presence Of the Pseudo Signal Peptide Of The Crf 2(a) R supporting

confidence: 91%

The Pseudo Signal Peptide of the Corticotropin-releasing Factor Receptor Type 2a Decreases Receptor Expression and Prevents Gi-mediated Inhibition of Adenylyl Cyclase Activity

Schulz

Rutz

Westendorf

et al. 2010

Journal of Biological Chemistry

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The corticotropin-releasing factor receptor type 2a (CRF 2(a) R) belongs to the family of G protein-coupled receptors. The receptor possesses an N-terminal pseudo signal peptide that is unable to mediate targeting of the nascent chain to the endoplasmic reticulum membrane during early receptor biogenesis. The pseudo signal peptide remains uncleaved and consequently forms an additional hydrophobic receptor domain with unknown function that is unique within the large G protein-coupled receptor protein family. Here, we have analyzed the functional significance of this domain in comparison with the conventional signal peptide of the homologous corticotropin-releasing factor receptor type 1 (CRF 1 R). We show that the presence of the pseudo signal peptide leads to a very low cell surface receptor expression of the CRF 2(a) R in comparison with the CRF 1 R. Moreover, whereas the presence of the pseudo signal peptide did not affect coupling to the G s protein, G i -mediated inhibition of adenylyl cyclase activity was abolished. The properties mediated by the pseudo signal peptide were entirely transferable to the CRF 1 R in signal peptide exchange experiments. Taken together, our results show that signal peptides do not only influence early protein biogenesis. In the case of the corticotropin-releasing factor receptor subtypes, the use of conventional and pseudo signal peptides have an unexpected influence on signal transduction.The family of corticotropin-releasing factor (CRF) 3 receptors encompasses two subtypes, the CRF 1 R and CRF 2 R (1, 2). The CRF 1 R is expressed mainly in the anterior pituitary and plays a central role in the regulation of the hypothalamic-pituitaryadrenal stress axis in mammals (3). It binds CRF with high affinity and mediates ACTH release from the pituitary leading to cortisol biosynthesis in the adrenal cortex. A large body of evidence points to a major role of the receptor in mediating CRF effects in anxiety and depressive disorders (4 -6).In the case of the CRF 2 R, three splice variants have been described as follows: the CRF 2(a) R, CRF 2(b) R, and CRF 2(c) R. All splice variants bind CRF with low affinity and the urocortins 1-3 with high affinity. They are involved in the regulation of feeding behavior (7) and in recovery from a stress response (8).It is likely that they are also involved in modulating anxietyrelated behavior.Both the CRF 1 R and the CRF 2(a) R usually couple to the G s / adenylyl cyclase system and consequently increase cytosolic cAMP as a second messenger. However, a promiscuous coupling behavior was described previously in particular for the CRF

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Section: The Presence Of the Pseudo Signal Peptide Of The Crf 2(a) R supporting

confidence: 91%

The Pseudo Signal Peptide of the Corticotropin-releasing Factor Receptor Type 2a Decreases Receptor Expression and Prevents Gi-mediated Inhibition of Adenylyl Cyclase Activity

Schulz

Rutz

Westendorf

et al. 2010

Journal of Biological Chemistry

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“…The human Y-79 retinablastoma cell line expresses functional CRF receptors [93] and presents a suitable model for the study of homologous desensitization and signal transduction pathways [94][95][96][97][98]. In this cell line, cytoprotective effects of CRF, involving suppression of pro-apoptotic pathways at a site upstream of activation of procaspase-3 and the involvement of PK A in the mediation of the anti-apoptotic effect of CRF, have been shown [99].…”

Section: Crf Signaling Pathways Related To Cancermentioning

confidence: 99%

The corticotropin releasing factor system in cancer: expression and pathophysiological implications

Kaprara

Pazaitou‐Panayiotou

Kortsaris

et al. 2010

Cell. Mol. Life Sci.

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Malignant tumors express multiple factors that have some role in the regulating networks supporting their ectopic growth. Recently, increased interest has been developing in the expression and biological role of the neuropeptides and receptors of the corticotropin releasing factor (CRF) system, the principal neuroendocrine mediator of the stress response, especially in the light of several R&D programs for small molecule antagonists that could present some anticancer therapeutic benefit. In the present article, we review the literature suggesting that the CRF system could be involved in the regulation of human cancer development. Potential implication in growth, metastasis, angiogenesis, or immune parameters via activation of locally expressed receptors could be clinically exploited by presenting targets of new therapeutic approaches.

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“…CRFR1 has recently been shown to couple to, and activate, multiple different G proteins, including G␣ s , G␣ i , G␣ q/11 , G␣ o , and G␣ z (13,14). However, CRFR1 is thought to preferentially couple to G␣ s leading to adenylyl cyclase activation and cAMP production, which func-tions to stimulate protein kinase A (4,(15)(16)(17)(18)(19).…”

Section: Corticotropin-releasing Factor (Crf)mentioning

confidence: 99%

Role of SAP97 Protein in the Regulation of Corticotropin-releasing Factor Receptor 1 Endocytosis and Extracellular Signal-regulated Kinase 1/2 Signaling

Dunn

Walther

Godin

et al. 2013

Journal of Biological Chemistry

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Background: CRFR1 regulates the physiological response to stress and is implicated in the manifestation of depression. Results: SAP97 interacts and co-localizes with CRFR1, suppresses CRFR1 endocytosis, and is required for CRFR1-mediated ERK1/2 phosphorylation. Conclusion: SAP97 functionally regulates CRFR1 trafficking and signaling. Significance: This is the first documentation of functional regulation of CRFR1 by a specific PDZ protein.

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Molecular Mechanisms of Corticotropin-Releasing Factor Receptor-Induced Calcium Signaling

Cited by 41 publications

References 39 publications

The Pseudo Signal Peptide of the Corticotropin-releasing Factor Receptor Type 2a Decreases Receptor Expression and Prevents Gi-mediated Inhibition of Adenylyl Cyclase Activity

The Pseudo Signal Peptide of the Corticotropin-releasing Factor Receptor Type 2a Decreases Receptor Expression and Prevents Gi-mediated Inhibition of Adenylyl Cyclase Activity

The corticotropin releasing factor system in cancer: expression and pathophysiological implications

Role of SAP97 Protein in the Regulation of Corticotropin-releasing Factor Receptor 1 Endocytosis and Extracellular Signal-regulated Kinase 1/2 Signaling

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