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Amitriptyline up‐regulates connexin43‐gap junction in rat cultured cortical astrocytes via activation of the p 38 and c ‐ Fos / AP ‐1 signalling pathway
Author(s) -
Morioka N,
Suekama K,
Zhang F F,
Kajitani N,
HisaokaNakashima K,
Takebayashi M,
Nakata Y
Publication year - 2014
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12614
Subject(s) - amitriptyline , intracellular , mapk/erk pathway , gap junction , connexin , microbiology and biotechnology , chemistry , phosphorylation , monoamine neurotransmitter , pharmacology , medicine , biology , endocrinology , receptor , biochemistry , serotonin
Background and Purpose Intercellular communication via gap junctions, comprised of connexin ( Cx ) proteins, allow for communication between astrocytes, which in turn is crucial for maintaining CNS homeostasis. The expression of Cx 43 is decreased in post‐mortem brains from patients with major depression. A potentially novel mechanism of tricyclic antidepressants is to increase the expression and functioning of gap junctions in astrocytes. Experimental Approach The effect of amitriptyline on the expression of Cx 43 and gap junction intercellular communication ( GJIC ) in rat primary cultured cortical astrocytes was investigated. We also investigated the role of p 38 MAPK intracellular signalling pathway in the amitriptyline‐induced expression of Cx 43 and GJIC . Key Results Treatment with amitriptyline for 48 h significantly up‐regulated Cx 43 mRNA , protein and GJIC . The up‐regulation of Cx 43 was not monoamine‐related since noradrenaline, 5‐HT and dopamine did not induce Cx 43 expression and pretreatment with α‐ and β‐adrenoceptor antagonists had no effect. Intracellular signalling involved p 38 MAPK, as amitriptyline significantly increased p 38 MAPK phosphorylation and Cx 43 expression and GJIC were significantly blocked by the p 38 inhibitor SB 202190. Furthermore, amitriptyline‐induced Cx 43 expression and GJIC were markedly reduced by transcription factor AP ‐1 inhibitors (curcumin and tanshinone IIA). The translocation of c‐Fos from the cytosol and the nucleus of cortical astrocytes was increased by amitriptyline, and this response was dependent on p 38 activity. Conclusion and Implication These findings indicate a novel mechanism of action of amitriptyline through cortical astrocytes, and further suggest that targeting this mechanism could lead to the development of a new class of antidepressants.