title: Involvement of histaminergic receptor mechanisms in the stimulation of NT-3 synthesis in astrocytes.
abstract: Neurotrophin-3 (NT-3) is produced by astrocytes, in addition to neurons, and monoamine neurotransmitters play a role in controlling NT-3 synthesis. The impact of histamine (HA) on the regulation of NT-3 synthesis in cultured astrocytes has not been studied. We evaluated the involvement of histamine receptors and intracellular mechanisms in the regulation of NT-3 production by HA. Real-time PCR was performed to examine the expression of all known histamine receptor subtypes in cultured rat cortical astrocytes. Pharmacological tools, selective for the H₁, H₂ and H₃ receptors and intracellular systems, were utilized to confirm functional properties of HA receptors in histaminergic up-regulation of astrocytic NT-3 synthesis. HA potently and transiently elevated NT-3 expression and protein levels by more than twofold. In addition to H₁ and H₂ receptors, cultured astrocytes also express H₃ receptors, which activate G(i/o) proteins to inhibit adenylyl cyclase and modulate MAP kinase activity. Histaminergic stimulation was partly inhibited by selective H₁, H₂, and H₃ antagonists whereas selective H₁, H₂, and H₃ agonists or mediators of the intracellular histaminergic pathways increased NT-3 levels. Inhibitors of PKA, PKC, and CaMK II significantly reduced the HA-induced increase in NT-3 cellular levels whereas the MAP kinase cascade inhibitor completely blocked the stimulatory action of HA and all selective agonists. In conclusion, the synthesis of astrocytic NT-3 stimulated by HA is a receptor-mediated process, which is fine-tuned via subtle modulation of parallel histaminergic H₁, H₂, and H₃ pathways that converge at the level of MAP kinase activity. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.
authors.affiliation: Department of Pharmacology and Experimental Toxicology, University of Ljubljana, Korytkova 2, SI-1000 Ljubljana, Slovenia. damijana-mojca.juric@mf.uni-lj.si
authors.forename: Damijana M
authors.initials: DM
authors.lastname: Jurič
authors.forename: Tina
authors.initials: T
authors.lastname: Mele
authors.forename: Marija
authors.initials: M
authors.lastname: Carman-Kržan
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D018929:Cell Culture Techniques; D002540:Cerebral Cortex / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D017442:Histamine Agonists / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D006635:Histamine H2 Antagonists / Q000494:pharmacology; D054828:Histamine H3 Antagonists / Q000494:pharmacology; D018377:Neurotransmitter Agents / Q000378:metabolism; D020933:Neurotrophin 3 / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011968:Receptors, Histamine / Q000378:metabolism*; D011969:Receptors, Histamine H1 / Q000378:metabolism; D011970:Receptors, Histamine H2 / Q000378:metabolism; D018100:Receptors, Histamine H3 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D017442:Histamine Agonists; D006634:Histamine H1 Antagonists; D006635:Histamine H2 Antagonists; D054828:Histamine H3 Antagonists; D018377:Neurotransmitter Agents; D020933:Neurotrophin 3; D012333:RNA, Messenger; D011968:Receptors, Histamine; D011969:Receptors, Histamine H1; D011970:Receptors, Histamine H2; D018100:Receptors, Histamine H3; D000242:Cyclic AMP