Cell-type specific calcium signaling by corticotropin-releasing factor type 1 (CRF1) and 2a (CRF2(a)) receptors: phospholipase C-mediated responses in human embryonic kidney 293 but not SK-N-MC neuroblastoma cells

Dautzenberg, Frank M.; Gutknecht, Eric; Linden, Ilse Van der; Olivares-Reyes, J. Alberto; Dürrenberger, Franz; Hauger, Richard L.

doi:10.1016/j.bcp.2004.07.013

Cited by 41 publications

(56 citation statements)

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“…Earlier (Dautzenberg et al, 2004), we demonstrated that ryanodine receptors are not involved in CRF agonist-mediated Ca 2ϩ mobilization. To show the direct involvement of the IP 3 Rs, HEK293 cells stably expressing hCRF 1 and hCRF 2(a) receptors were incubated with 100 M concentration of the IP 3 R antagonist 2-aminoethoxydiphenyl borate (2-APB).…”

Section: And B)mentioning

confidence: 71%

“…The stable hCRF 1 -HEK and hCRF 2(a) -HEK cell lines were established as described previously (Dautzenberg et al, 2004). Cells were kept in DMEM supplemented with 10% fetal bovine serum (FBS) and 500 g/ml Geneticin as selection marker (Invitrogen).…”

Section: Methodsmentioning

confidence: 99%

“…In a previous study (Dautzenberg et al, 2004), we reported on the ability of the two CRF receptors hCRF 1 and hCRF 2(a) to mobilize Ca 2ϩ in recombinant HEK293 cells but not in recombinant SK-N-MC neuroblastoma cells. This sheds light on the importance of the cellular background for the specificity of CRF receptor signaling.…”

mentioning

confidence: 97%

“…CRF 1 and CRF 2 receptors mainly couple to the stimulatory G s protein, which activates adenylate cyclases and subsequently the cAMP second-messenger cascade . We and others have reported that, despite their coupling to G s , CRF receptors also stimulate transient calcium (Ca 2ϩ ) mobilization in certain cell types by phospholipase C (PLC) activation in vitro (Dautzenberg et al, 2004) and protein kinase C activation in vivo (Blank et al, 2003). PLC activation through G-protein-coupled receptors is generally believed to be mediated by coupling to the G q protein, but the involvement of the G␤␥ subunits of the inhibitory G i and G o proteins has been reported as well (Rhee, 2001).…”

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confidence: 99%

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

Gutknecht¹,

Linden²,

Kolen³

et al. 2008

Mol Pharmacol

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The molecular mechanisms governing calcium signal transduction of corticotropin-releasing factor (CRF) receptors CRF 1 and CRF 2(a) stably expressed in human embryonic kidney (HEK) 293 cells were investigated. Calcium signaling strictly depended on intracellular calcium sources, and this is the first study to establish a prominent contribution of the three major G-protein families to CRF receptor-mediated calcium signaling. Overexpression of G␣ q/11 and G␣ 16 led to leftward shifts of the agonist concentration-response curves. Blockade of G␣ q/11 proteins by the small interfering RNA (siRNA) technology partially reduced agonist-mediated calcium responses in CRF 1 -and CRF 2(a) -expressing HEK293 cells, thereby proving a contribution of the G q protein family. A small but significant inhibition of calcium signaling was recorded by pharmacological inhibition of G i/o proteins with pertussis toxin treatment. This effect was mediated by direct binding of G␤␥ subunits to phospholipase C. G i/o inhibition also elevated cAMP responses in CRF receptor-overexpressing HEK293 cells and in Y79 retinoblastoma cells endogenously expressing human CRF 1 and CRF 2(a)

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Section: And B)mentioning

confidence: 71%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 97%

mentioning

confidence: 99%

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

Gutknecht¹,

Linden²,

Kolen³

et al. 2008

Mol Pharmacol

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“…65 Furthermore, following peptide binding, CRF1 and the CRF2 could alter the intracellular Ca 2+ signaling through Gαq-mediated or Gβγ-mediated stimulation of phospholipace C (PLC). 63,66 Moreover, the CRF receptor-mediated activation of Gβγ-subunits has been shown to stimulate the phosphatidylinositol 3-kinase, which, through the production of PI (3,4,5) P3, activates the PLC, thus resulting in the mobilization of Ca 2+ . 63 The CRF1-mediated activation of PI3-K and PLC pathways, as well as mobilization of intracellular calcium stores, has been shown to activate ERK1/2.…”

Section: -57mentioning

confidence: 99%

The “homeostasis hormone” and its CRF1 receptor. From structure to function

Fahmy¹,

Spyridaki²,

Kuppast³

et al. 2012

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Agonist bias and agonist‐dependent antagonism at corticotrophin releasing factor receptors

Tasma

Wills

Hay

et al. 2020

Pharmacology Res & Perspec

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The corticotropin-releasing factor (CRF) receptors represent potential drug targets for the treatment of anxiety, stress, and other disorders. However, it is not known if endogenous CRF receptor agonists display biased signaling, how effective CRF receptor antagonists are at blocking different agonists and signaling pathways or how receptor activity-modifying proteins (RAMPs) effect these processes. This study aimed to address this by investigating agonist and antagonist action at CRF 1 and CRF 2 receptors. We used CRF 1 and CRF 2 receptor transfected Cos7 cells to assess the ability of CRF and urocortin (UCN) peptides to activate cAMP, inositol monophosphate (IP 1 ), and extracellular signal-regulated kinase 1/2 signaling and determined the ability of antagonists to block agonist-stimulated cAMP and IP 1 accumulation. The ability of RAMPs to interact with CRF receptors was also examined. At the CRF 1 receptor, CRF and UCN1 activated signaling in the same manner. However, at the CRF 2 receptor, UCN1 and UCN2 displayed similar signaling profiles, whereas CRF and UCN3 displayed bias away from IP 1 accumulation over cAMP. The antagonist potency was dependent on the receptor, agonist, and signaling pathway. CRF 1 and CRF 2 receptors had no effect on RAMP1 or RAMP2 surface expression. The presence of biased agonism and agonist-dependent antagonism at the CRF receptors offers new avenues for developing drugs tailored to activate a specific signaling pathway or block a specific agonist. Our findings suggest that the already complex CRF receptor pharmacology may be underappreciated and requires further investigation. K E Y W O R D Scorticotropin releasing factor, CRF 1 , CRF 2 , functional selectivity, intracellular signaling, probedependent antagonism Note: Relative efficacy and signaling bias were calculated using UCN1 and cAMP as the reference agonist and signaling pathway. Data were analyzed using a student's t test (CRF 1 ) or by one-way ANOVA followed by a post-hoc Dunnett's test (CRF 2 ).Data are mean ± SEM of the combined data from 5 independent experiments.Abbeviations: CRF, corticotropin releasing factor; ERK1/2, extracellular signal-regulated kinase 1/2; IP 1 , inositol monophosphate.*P < .05 compared to UCN1. S U PP O RTI N G I N FO R M ATI O NAdditional supporting information may be found online in the Supporting Information section.How to cite this article: Tasma Z, Wills P, Hay DL, Walker CS.Agonist bias and agonist-dependent antagonism at corticotrophin releasing factor receptors. Pharmacol Res Perspect. 2020;e00595. https://doi.

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Cell-type specific calcium signaling by corticotropin-releasing factor type 1 (CRF1) and 2a (CRF2(a)) receptors: phospholipase C-mediated responses in human embryonic kidney 293 but not SK-N-MC neuroblastoma cells

Cited by 41 publications

References 41 publications

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

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

The “homeostasis hormone” and its CRF1 receptor. From structure to function

Agonist bias and agonist‐dependent antagonism at corticotrophin releasing factor receptors

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