The role of histamine H1, H2 and H3 receptors 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. We evaluated the active involvement of histamine receptors and intracellular mechanisms in the regulation of NT‐3 production by HA.HA (1 μM) significantly and transiently elevated NT‐3 mRNA levels by 2.2‐fold after 30 min of incubation following by 2.1‐fold increase in NT‐3 intracellular levels after 6 h. Its stimulation was partly inhibited by selective H1, H2 and H3 antagonists. NT‐3 levels in astrocytes were increased by selective H1, H2 and H3 agonists as well as by adenylyl cyclase activation, PKA activation, PKC activation and mobilization of intracellular Ca2+. HA‐induced increase in NT‐3 cellular levels were significantly reduced by H‐89, staurosporin, KN‐62 and desensitizing pretreatment with TPA. MAP kinase cascade inhibitor PD98059 completely blocked the stimulatory action of HA and all selective agonists. Using quantitative RT‐PCR we confirmed that cultured rat cortical astrocytes express not only H1 and H2 receptors already identified by radioligand binding studies but also H3 receptors which were sensitive to pertussis toxin. In conclusion, the synthesis of astrocytic NT‐3 stimulated by HA is an adaptable process using several parallel histaminergic pathways using H1‐, H2‐, and H3‐receptor pathways. The observed H1, H2 and H3 receptor crosstalk in histaminergic regulation of NT‐3 leads to the convergence of these pathways at the level of MAP kinase activity which in the next step triggers the increased expression and subsequently the synthesis of NT‐3 in astrocytes.