Modulation of c-Jun N-terminal kinase signaling and speciﬁc
glucocorticoid receptor phosphorylation in the treatment of major
Milica J. Jovicic
, Iva Lukic
, Marija Radojcic
, Miroslav Adzic
, Nadja P. Maric
School of Medicine, University of Belgrade, Serbia
Department of Molecular Biology and Endocrinology, VINCA Institute of Nuclear Sciences, University of Belgrade, Serbia
Clinic for Psychiatry, Clinical Center of Serbia, Belgrade, Serbia
Received 19 April 2015
Accepted 27 May 2015
Glucocorticoid resistance is a common ﬁnding in major depressive disorder. Increased glucocorticoid
receptor (GR) phosphorylation at serine 226 is associated with increased glucocorticoid resistance.
Previously we have demonstrated that depressed patients exhibit higher levels of GR phosphorylated
at serine 226 compared to healthy controls. The enzyme that is involved in this speciﬁc GR phosphory-
lation is c-Jun N-terminal kinase (JNK). We propose that modulation of glucocorticoid phosphorylation at
serine 226, by targeting JNK signaling pathway, could be a potential strategy for antidepressant treat-
ment. We base this assumption on the results of previous research that examined GR phosphorylation
and JNK signaling in animal models and human studies. We also discuss the potential challenges in tar-
geting JNK signaling pathway in depression.
Ó 2015 Elsevier Ltd. All rights reserved.
The etiology of depression is still poorly understood, and pre-
sent treatment strategies fail to alleviate the symptoms of 10–
40% of depressed individuals . Current trends in mood disorders
research highlight the need of distinguishing between the speciﬁc
syndromes that fall under the wide ‘‘umbrella’’ of major depres-
sion, in order to personalize treatment and achieve better thera-
peutic response. This notion found support in basic research,
which demonstrated signiﬁcantly different gene expression pro-
ﬁles between stress-related depression models and endogenous
depression models .
Dysregulation of the hypothalamic–pituitary–adrenal (HPA)
axis has long been associated with stress-related depression .
Namely, a signiﬁcant percentage of depressed patients exhibit
increased blood cortisol levels, and this effect is higher in those
with comorbid anxiety [4,5]. Effects of cortisol are mediated
through the glucocorticoid receptor (GR), including the feedback
regulation of the HPA axis. Therefore, the impairment of GR
signaling is suggested to play a pivotal role in the HPA axis dysreg-
ulation in stress-related depression [6,7].
The GR regulates the expression of a variety of genes, including
ones that are involved in metabolism and immunity, neuronal sur-
vival, neurogenesis and regulation of HPA axis . Therefore, in
addition to its role in the neuroendocrine system, GR signaling is
strongly involved in immune system response. Cortisol is one of
the most potent anti-inﬂammatory hormones in the body, and
pathways coupled with glucocorticoid resistance may conspire
during chronic stress to contribute to chronic activation of inﬂam-
matory responses . Namely, a large body of research supports
the notion of inﬂammatory disturbance in depression [10,11].
Chronic stress, through glucocorticoid resistance (i.e. decreased
sensitivity to anti-inﬂammatory effects of glucocorticoids), may
contribute to chronic activation of immune system in major
depressive disorder .
Considering the complex interplay between glucocorticoid and
inﬂammatory signaling (in both physiological and pathological
conditions), as well as evidence of dysfunction of both these sys-
tems in major depression, targeting one or both systems could be
a potential therapeutic strategy for this disorder .
The glucocorticoid receptor signaling
GR is a ligand-dependent transcriptional factor that resides in
the cell cytoplasm in its inactive form. After ligand binding it
0306-9877/Ó 2015 Elsevier Ltd. All rights reserved.
Sources of support: Researchers received Grant support from the Ministry of
Education, Science and Technological Development, Republic of Serbia (Project
Corresponding author at: Clinic for Psychiatry, Clinical Center of Serbia,
Pasterova 2, 11000 Belgrade, Serbia. Tel./fax: +381 11 3065637.
E-mail address: email@example.com (N.P. Maric).
Medical Hypotheses 85 (2015) 291–294
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