Tina Mele, Damijana M. Jurič
Department of Pharmacology and Experimental Toxicology, Faculty of Medicine, University of Ljubljana, Slovenia
Histamine (HA) is an important neurotransmitter and neuromodulator in the brain. Astrocytes express histamine H1 and H2 receptors thus indicating the existence of a functional role of HA in these cells. Astrocytes produce neurotrophin-3 (NT-3), which is susceptible to regulation by the monoamine neurotransmitters (Mele et al., 2010). So far, the impact of HA on the regulation of astrocytic NT-3 synthesis has not been studied in detail.
HA potently and transiently elevates NT-3 expression and protein levels in cultured rat cortical astrocytes. As shown by real-time PCR and binding studies, in addition to H1 and H2 receptors astrocytes express also H3 receptor. The identified receptor is coupled to Gi/o protein to inhibit adenylyl cyclase, modulate PLC/PKC (but not CAMK II) signaling and MAP kinase activity. Using pharmacological tools, selective for histamine receptors and intracelullar systems, it was demonstrated that not only H1 and H2 receptors but also H3 receptor significantly participates in the stimulatory effect of HA on NT-3.
In conclusion, the synthesis of astrocytic NT-3 induced by HA is a receptor-mediated process, which is fine-tuned via subtle modulation of parallel histaminergic pathways: H1/PLC/PKC/CaMKII, H2/cAMP/PKA and the novel H3/Gi/o-protein/PKC pathway. H1, H2 and H3 receptor cascades converge at the level of MAP kinase activity (Jurič et al., 2011, in press).
Keywords: histamine, histamine H3 receptor, neurotrophin-3, astrocytes