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The calcineurin—nuclear factor of activated T cells signaling pathway mediates the effect of corticotropin releasing factor and urocortins on catecholamine synthesis
Author(s) -
Dermitzaki Eirini,
Tsatsanis Christos,
Gravanis Achille,
Margioris Andrew N.
Publication year - 2012
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.22914
Subject(s) - nfat , calcineurin , microbiology and biotechnology , medicine , catecholamine , endocrinology , chemistry , biology , transplantation
Abstract The biological effects of the Corticotropin‐releasing factor (CRF) family of neuropeptides are mediated by mobilization of [Ca 2+ ]. Aim of the current work was to examine if the calcineurin/NFAT (nuclear factor of activated T‐cells) signaling pathway is involved in the effect of CRF peptides in catecholamine synthesis and secretion from PC12 rat pheochromocytona cells, a model for the study of adrenal catecholamine production. PC12 cells express both types of CRF receptors. Our data are as follows: (a) The calcineurin inhibitor cyclosporine A (CsA) blocked norepinephrine secretion induced by ligands of either CRF type 1 (CRF 1 ) or 2 (CRF 2 ) receptors on PC12 cells. (b) Silencing NFAT2 expression using a selective NFAT2 siRNA blocked CRF 1 and CRF 2 ‐induced NE production. (c) CRF ligands induced NFAT transcriptional activity in cells transfected with a luciferase reporter construct controlled by NFAT binding elements (NFAT‐Luc). (d) CsA completely blocked the stimulatory effect of CRF 1 and CRF 2 ligands on NFAT activity in NFAT‐Luc transfected cells. (e) PKA, PKC, p38‐MAPK, Tpl2, Ha‐Ras, and AKT1 were crucial intermediates for both CRF 1 and CRF 2 ‐induced NFAT activation. Interestingly, MEK1/2 and ERK1/2 were crucial only for the CRF 2 ‐induced NFAT activation. (f) p38‐MAPK and Tpl2 were crucial intermediates for both CRF 1 and CRF 2 ‐induced norepinephrine production, while AKT1 affected only CRF 2 ‐induced norepinephrine production. In conclusion, our data suggest that CRF 1 and CRF 2 ligands activate the transcription factor NFAT and its activation is prerequisite for CRF‐induced catecholamine production from chromaffin cells. J. Cell. Physiol. 227: 1861–1872, 2012. © 2011 Wiley Periodicals, Inc.