Activation of 5-HT Receptors That Stimulate the Adenylyl Cyclase Pathway Positively Regulates IGF-I in Cultured Craniofacial Mesenchymal CellsLambert H.W.a,b · Weiss E.R.a · Lauder J.M.a
aDepartment of Cell Biology and Anatomy, University of North Carolina School of Medicine, Chapel Hill, N.C., and bDepartment of Cell Biology, Vanderbilt University School of Medicine, Nashville, Tenn., USA Dev Neurosci 2001;23:70–77 (DOI:10.1159/000048697)
Results of the present study demonstrate that activation of the adenylyl cyclase/protein kinase A (PKA) pathway leads to increased levels of insulin-like growth factor I (IGF-I) in cultured embryonic mouse mandibular mesenchymal cells. Treatment of serum-free cultures with 10–8M 8-OH-DPAT (DPAT) or with 10–5M forskolin in the presence of the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX; 10–5M) increased levels of IGF-I (but not IGF-II), as measured by [125I]protein A immunobinding. In a previous study, we showed that DPAT, forskolin, IBMX and the 5-HT4 receptor agonist SC53116 all increased the synthesis of cyclic adenosine monophosphate (cAMP) in these cultures. Taken together, these results provide evidence that stimulation of the adenylyl cyclase/PKA pathway in embryonic mandibular mesenchymal cells positively regulates IGF-I. This is supported by the ability of the PKA inhibitor Rp-cAMPS to block increases in IGF-I caused by both DPAT and forskolin. Consistent with these results, DPAT and forskolin increased phosphorylation of the cAMP response element binding protein (CREB), which was also blocked by Rp-cAMPS. These results suggest that activation of 5-HT receptors positively coupled to the adenylyl cyclase/PKA pathway may promote transcription of IGF-I through a cAMP response element (CRE) in the IGF-I promoter. This may represent one mechanism whereby 5-HT positively regulates IGF-I expression in developing craniofacial mesenchymal cells.
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