Serotonin receptor agonists that increase cyclic AMP positively regulate IGF-I in mouse mandibular mesenchymal cells

Evidence from the present study suggests th at activation of both 5-HT1A an d 5-HT4 (5-hydroxytryptamine) receptor subtypes stimulates cyclic adenosine monophosphate (cAMP) synthesis in cultured embryonic mouse mandibular mese nchymal cells (micromass cultures). When these cells were grown in serum-fr ee medium and treated with 10(-8) M agonist selective for either the 5-HT1A or 5-HT4 receptor subtype (8-OH-DPAT and SC53116, respectively), this sign ificantly stimulated cAMP synthesis and increased insulin-like growth facto r I (IGF-I), but not IGF-II, protein levels compared to vehicle-treated con trols, as measured by semi-quantitative immunobinding: assays. Consistent w ith these results, IGF-I was significantly decreased when mandibular mesenc hymal cells were grown in serum-containing medium (which contains micromola r amounts of 5-HT from fetal calf serum) and treated with 10(-8) M antagoni st selective for the 5-HT1A Or 5-HT4 receptor subtype (NAN-190 on SDZ-205,5 57). Forskolin also stimulated cAMP and IGF-I (but not IGF-II) in both seru m-containing and serum-free cultures. These results indicate that activatio n of 5-HT receptors that increase cAMP promotes synthesis of IGF-I. This ma y occur by activation of the cAMP response element sequence present in the IGF-I promoter region. Stimulation of the adenylyl cyclase pathway by activ ation of 5-HT1A or 5-HT4 receptors may be one mechanism by which serotonin regulates IGF-I synthesis in developing craniofacial mesenchymal cells.