Dioxin-Mediated Up-Regulation of Aryl Hydrocarbon Receptor Target Genes Is Dependent on the Calcium/Calmodulin/CaMKIα Pathway

Induction of Intracellular Calcium Concentration by Environmental Benzo(a)pyrene Involves a β2-Adrenergic Receptor/Adenylyl Cyclase/Epac-1/Inositol 1,4,5-Trisphosphate Pathway in Endothelial Cells

“…For example, inhibition of the Ca 2ϩ signal evoked by PAHs fully prevents their AhR-related inducing effects toward CYP1A1 or CCL1 expression (5). These data suggest that calcium is a major player of the AhR-signaling pathway activated by PAHs (5,6). Early PAH-related calcium mobilization, however, occurs independently of AhR.…”

“…Indeed, inhibition of the terminal step of calcium release from intracellular stores through the use of 2-APB was sufficient for inhibiting CYP1B1 induction in HMEC-1 cells exposed to B(a)P. Similarly, 2-APB and the calcium chelating agent 1,2-bis(2-aminophenoxy)ethane-N,N,NЈ,NЈ-tetraacetic acid tetrakis have been shown to prevent the up-regulation of various AhR targets such as CYP1A1 and the chemokine CCL1 in response to AhR agonists (5,6,12). The exact way that calcium interacts with the AhR-signaling cascade remains to be determined, even if a role for calcium-activated signaling pathways such as calmodulindependent protein kinases may be suspected (6,51). In addition to calcium, cAMP may also play a role in the AhR signaling cascade, because cAMP and its downstream kinase PKA have been reported to constitute players of the AhR pathway by themselves (20,52).…”

Activation of the Aryl Hydrocarbon Receptor by the Calcium/Calmodulin-Dependent Protein Kinase Kinase Inhibitor 7-Oxo-7H-benzimidazo[2,1-a]benz[de]isoquinoline-3-carboxylic Acid (STO-609)

“…Variations in [Ca 2ϩ ] i were analyzed by spectrofluorometry using the Ca 2ϩ -sensitive probe Fura-2-AM, as previously reported (Monteiro et al, 2008). In brief, MCF-7 cells were cultured in 24-well plates and incubated with 1.5 M of the acetoxy cell-permeant form of Fura-2 (Fura-2-AM), for 30 min at 37°C in HEPES-buffered medium (10 mM HEPES, 134.8 mM NaCl, 4.7 mM KCl, 1 mM MgCl 2 , 1.2 mM KH 2 PO 4 , 1 mM CaCl 2 , 10 mM glucose, pH 7.4, at 37°C), supplemented with 0.006% Pluronic acid.…”

“…Indeed, TCDD has been shown to activate this kinase, whose chemical inhibition or knockdown of expression abolished TCDD-triggered up-regulation of various AhR gene targets. Cellular and molecular mechanisms responsible for the activation of CaMKI␣ by AhR ligands remain unknown, even if they have been presumed to be linked to the fast elevation of [Ca 2ϩ ] i and putative subsequent calmodulin activation triggered by AhR ligands (Monteiro et al, 2008). Moreover, involvement of upstream activators of CaMKI, CaMK kinases ␣ and ␤, that constitute important players of the CaMKI signaling cascade (Hook and Means, 2001), may be suspected.…”

“…In addition, the Ca 2ϩ /calmodulindependent protein kinase (CaMK) I␣ has been recently recognized as a contributing factor to AhR-mediated genomic response (Monteiro et al, 2008). Indeed, TCDD has been shown to activate this kinase, whose chemical inhibition or knockdown of expression abolished TCDD-triggered up-regulation of various AhR gene targets.…”