title: Neurotensin negatively modulates Akt activity in neurotensin receptor-1-transfected AV12 cells.
abstract: 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.
authors.affiliation: Lilly Research Laboratories, Indianapolis, Indiana 46225, USA. liu_feng@lilly.com
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.forename: Peiyi
authors.initials: P
authors.lastname: Yang
authors.forename: Melvyn
authors.initials: M
authors.lastname: Baez
authors.forename: Binhui
authors.initials: B
authors.lastname: Ni
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002772:Cholera Toxin / Q000494:pharmacology; D006224:Cricetinae; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D007329:Insulin Antagonists / Q000737:chemistry / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D009496:Neurotensin / Q000737:chemistry / Q000494:pharmacology*; D037342:Pertussis Toxin / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D018028:Receptors, Neurotensin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D014162:Transfection
chemical_list: D007328:Insulin; D007329:Insulin Antagonists; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D018028:Receptors, Neurotensin; D013449:Sulfonamides; C114036:neurotensin type 1 receptor; D009496:Neurotensin; D004815:Epidermal Growth Factor; D002772:Cholera Toxin; D037342:Pertussis Toxin; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide