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Neurotensin negatively modulates Akt activity in neurotensin receptor‐1‐transfected AV12 cells
Author(s) -
Liu Feng,
Yang Peiyi,
Baez Melvyn,
Ni Binhui
Publication year - 2004
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.20098
Subject(s) - protein kinase b , neurotensin , microbiology and biotechnology , neurotensin receptor , pi3k/akt/mtor pathway , signal transduction , chemistry , g protein coupled receptor , biology , receptor , endocrinology , medicine , biochemistry , neuropeptide
Neurotensin (NT) regulates a variety of biological processes primarily through interaction with neurotensin receptor‐1 (NTR1), a heterotrimeric G‐protein‐coupled receptor (GPCR). Stimulation of NTR1 has been linked to activation of multiple signaling transduction pathways via specific coupling to G q , G i/o , or G s , in various cell systems. However, the function of NT/NTR1 in the regulation of the Akt pathway remains unknown. Here, we report that activation of NTR1 by NT inhibits Akt activity as determined by the dephosphorylation of Akt at both Ser473 and Thr308 in AV12 cells constitutively expressing human NTR1 (NTR1/AV12). The inactivation of Akt by NT was rapid and dose‐dependent. This effect of NT was completely blocked by the specific NTR1 antagonist, ( S )‐(+)‐[1‐(7‐chloro‐4‐quinolinyl)‐5‐(2,6‐dimethoxyphenyl)pyrazol‐3‐yl)‐carbonylamino] cyclohexylacetic acid (SR 48527), but unaffected by the less active enantiomer (( R )‐(−)‐[1‐(7‐chloro‐4‐quinolinyl)‐5‐(2,6‐dimethoxyphenyl)pyrazol‐3‐yl)‐carbonylamino] cyclohexylacetic acid (SR 49711)), indicating the stereospecificity of NTR1 in the negative regulation of Akt. In addition, NT prevented insulin‐ and epidermal growth factor (EGF)‐mediated Akt activation. Our results provide insight into the role of NT in the modulation of Akt signaling and the potential physiological significance of Akt regulation by NT. © 2004 Wiley‐Liss, Inc.