Involvement of histaminergic receptor mechanisms in the stimulation of NT-3 synthesis in astrocytes

• Published in: Neuropharmacology Vol. 60; no. 7; pp. 1309 - 1317
• Main Authors: Jurič, Damijana M., Mele, Tina, Čarman-Kržan, Marija
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.06.2011
• Subjects: Adenylate cyclase; Animals; Antagonists; Astrocytes; Astrocytes - drug effects; Astrocytes - metabolism; Ca super(2+)/calmodulin-dependent protein kinase II; Cell Culture Techniques; Cerebral Cortex - metabolism; Cyclic AMP - metabolism; Histamine; Histamine Agonists - pharmacology; Histamine H 3 receptor; Histamine H1 Antagonists - pharmacology; Histamine H2 Antagonists - pharmacology; Histamine H2 receptors; Histamine H3 Antagonists - pharmacology; Histamine H3 receptors; Histamine receptor; Histamine receptors; MAP kinase; Memory; monoamines; Neurons; Neurotransmitter Agents - metabolism; Neurotransmitters; Neurotrophin 3; Neurotrophin 3 - biosynthesis; Polymerase chain reaction; Protein kinase A; Protein kinase C; Rat; Rats; Rats, Wistar; Receptor mechanisms; Receptors, Histamine - metabolism; Receptors, Histamine H1 - metabolism; Receptors, Histamine H2 - metabolism; Receptors, Histamine H3 - metabolism; RNA, Messenger - metabolism; Signal Transduction - physiology; Histamine; Neurotrophin-3; Histamine receptor; Rat; Histamine H 3 receptor; Astrocytes
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2011.01.019

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 H 1, H 2 and H 3 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 H 1 and H 2 receptors, cultured astrocytes also express H 3 receptors, which activate G i/o proteins to inhibit adenylyl cyclase and modulate MAP kinase activity. Histaminergic stimulation was partly inhibited by selective H 1, H 2, and H 3 antagonists whereas selective H 1, H 2, and H 3 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 H 1, H 2, and H 3 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’. ► We evaluated the functional interplay of HA and its receptors in NT-3 synthesis. ► HA potently and transiently increases astrocytic NT-3 expression and protein levels. ► In addition to H 1 and H 2 receptors, cultured astrocytes express H 3 receptors. ► H 3 receptors via G i/o proteins inhibit adenylyl cyclase and modulate MAPK activity. ► Parallel histaminergic pathways modulate HA-induced NT-3 synthesis in astrocytes.