Histamine, a biogenic amine related to the amino acid histidine, is best known for its role in allergic reactions, during which it is released by mast cells to cause vasodilation and the all-too-familiar runny nose and watery eyes. The fact that histamine also has an important function as a neurotransmitter is less well known. For example, cells in the visual system of Drosophila respond to histamine, and this molecule is regarded as one of the main transmitters in the eye of the fly. Unfortunately, we know very little about the receptor that mediates this effect of histamine, apart from the fact that it is an unidentified chloride channel. But now two papers report the discovery of two cDNAs from Drosophila that code for a pair of histamine-gated chloride channels that might just be the missing receptor.

As ligand-gated ion channels share several structural features, Gisselmann et al. searched the Drosophila genome for new molecules that belong to this channel superfamily. They identified several sequences that could potentially encode ligand-gated channels, expressed them in Xenopus oocytes, and tested their sensitivity to histamine. This approach led the authors to discover two histamine-gated, chloride-permeable channels: DM-HisCl-α1 and -α2. The properties of these channels, especially those of DM-HisCl-α1, partly matched the known characteristics of the native Drosophila receptor. So, DM-HisCl-α1 (but not -α2) was present in the Drosophila eye, and the pharmacological profile of both recombinant channels was similar to that of the native channel. Using a related approach, Zheng et al. made similar observations and further provided evidence that the two proteins can assemble to form heteromeric channels.

Although so-called 'histaminergic' pathways have been described in the mammalian brain, they have not received as much experimental attention as other transmitter systems, partly because the tools available to study them have not allowed us to answer many challenging questions. Metabotropic histamine receptors have been identified in mammals, but it is now tempting to speculate that channels similar to those reported in these two papers might also exist in the mammalian brain. Their findings should certainly rekindle our interest in the role of histamine in mammalian neurotransmission.