Histamine functions as a key neurotransmitter in

Histamine functions as a key neurotransmitter in multiple circuits to control various behaviors. In Drosophila photoreceptor, histamine is produced de novo by histidine decarboxylase (Burg et al., 1993); meanwhile, maintaining normal histamine content also depends on the histamine recycling pathway (Borycz et al., 2002, Chaturvedi et al., 2016, Stenesen et al., 2015, Xu et al., 2015). In both pathways, loading histamine into synaptic vesicles is critical for histaminergic neurotransmission (Figure 4). The absence of VMAT in some histaminergic neurons, including fly photoreceptors, suggests the existence of VMAT-independent vesicular transport of histamine. Here, we found a putative vesicular histamine transporter LOVIT in photoreceptor synaptic vesicles, providing the first evidence that a vesicular monoamine transporter other than VMAT protein may exist. It is speculated that other species may use a similar transporter to regulate the location of monoamines.
STAR★Methods
Acknowledgments We thank Dr. Janusz Borycz for helping with the experiments and for helpful suggestions and discussions. We are indebted to Dr. Ian A. Meinertzhagen for many helpful discussions and comments on the manuscript. We thank the Bloomington Stock Center, Tsinghua Fly Center, Vienna Drosophila Resource Center, Dr. C. Montell and S. Carroll, and the Developmental Studies Hybridoma Bank for reagents. We thank the Imaging Center at the Institute of Biophysics, Chinese Academy of Sciences, for EM section observations. We also thank the National Protein Science Facility at Tsinghua University and the Antibody Center at NIBS for technical assistance. This work was supported by a grant from the National Natural Science Foundation of China (81670891) and by a “973” grant (2014CB849700) from the Chinese Ministry of Science awarded to T.W. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Introduction Histamine [2-(4-Imidazolyl)-ethylamine] is an important mediator of many physiological and pathological processes including inflammation, gastric Forskolin receptor secretion, neuromodulation, regulation of immune function, cell proliferation and differentiation, among others. Histamine exerts its biological effects by binding to four different G protein-coupled receptor subtypes (H1-H4) (Panula et al., 2015). Until now, the most clinically relevant uses of histamine receptor ligands are achieved through the interaction with histamine H1 or H2 receptors, which are widely expressed in many tissues. In this regard, histamine H1 receptor antagonists/inverse agonists are used in the treatment of several allergic conditions, such as rhinoconjunctivitis, urticaria, and atopic dermatitis, and are promptly available as prescription and/or as over-the-counter drugs (Church, 2016). On the other hand, histamine H2 receptor antagonists/inverse agonists have proved to be active agents for the treatment of duodenal and gastric ulcers, reflux, esophagitis and Zollinger–Ellison syndrome (Hershcovici and Fass, 2011, Sigterman et al., 2013). Additionally, since histaminergic ligands are low-cost drugs with no patent protection, there is a great interest to facilitate the repurposing of these drugs for other pathologies. Consequently, a deep understanding of their mechanisms of action is needed. The histamine H1 and H2 receptors are coexpressed in most human tissues and cell types, such as neurons, airway and vascular smooth muscle cells, endothelial cells, hepatocytes, epithelial cells, neutrophils, eosinophils, monocytes, dendritic cells, as well as T and B lymphocytes, among others (Jutel et al., 2009, Parsons and Ganellin, 2009). In most tissues, histamine H1 receptor couples to Gαq/11 leading to an increase in phosphoinositide metabolism, whereas histamine H2 receptor couples to Gαs, triggering adenylyl cyclase (AC) activation and cyclic AMP (cAMP) accumulation (Panula et al., 2015). In these systems, the action of endogenous histamine may result from the balance and coordination of the signaling events activated by these, or even more, subtypes of histamine receptors. In this way, previous studies of our laboratory have described the existence of histamine H1 and H2 receptor crossregulation. In native and recombinant systems, both receptors desensitize when cells are exposed to a sustained stimulus with histamine H1 or H2 receptor agonists. Interestingly, this crossdesensitization does not depend on second messengers nor their downstream kinases, PKA or PKC, but on G protein-coupled receptor kinase 2 (GRK2) (Alonso et al., 2013). In addition, upon activation of histamine H1 or H2 receptor, both cointernalize in endosomes and form heteromers. Since these crossregulation mechanisms proved to be critical for the output response to histaminergic stimulation, it would be expected that it also affects the response of the histamine H1 and H2 receptor inverse agonists used in the clinic.