In brain, histamine (HA) is the transmitter of a neuronal system resembling other monoaminergic systems. It is also present in mast cells from which it may control vascular and inflammatory processes. Its various actions are mediated not only by the two well known H1- and H2-receptor subclasses but also by the recently discovered H3-receptors, with distinct localization and pharmacology. H1-receptors mediate a series of biochemical responses which have several features in common: they require intact cells to be observed and largely depend upon the availability of Ca2+. H1-receptor-mediated responses include glycogenolysis, stimulation of cyclic GMP formation, potentiation of cyclic AMP formation. Recent studies indicate that H1-receptors are linked with phosphatidylinositol breakdown and generation of two intracellular signals which both contribute to the final response (e.g. in the cyclic AMP generation). H2-receptors seem to be directly linked with an adenylate cyclase and their stimulation results in enhanced electrophysiologically recorded responses to excitatory agents. Finally whereas H1- and H2-receptors appear to be postsynaptically located, a novel subclass (H3) of HA receptors was recently revealed with a presynaptic localization. H3-receptors are autoreceptors mediating inhibition of HA release from and biosynthesis in histaminergic nerve terminals in the CNS. The physiological and pharmacological implications of three distinct receptor subclasses for HA will be discussed.

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