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  • br Conclusion br Acknowledgement br


    Introduction Biogenic amine histamine is synthesized from L-histidine by histidine decarboxylase (HDC). Histamine is involved in a wide variety of pathological and physiological processes including allergic reactions, inflammation, immune responses, gastric secretion, and neurotransmission. Intracellularly synthetized histamine is stored in cytoplasmic granules of mast (+)-Aphidicolin and basophils, two of the major producers of histamine. Basophilic leukemia (RBL)-2H3 cells, a tumor analog of rat mast cells, is considered to be a convenient model to study immunoglobulin E (IgE)-mediated degranulation of mast cells, because they express the IgE receptor, store mediators in granules, and release mediators, such as histamine, β-hexosaminidase, and serotonin, after crosslinking IgE (Maeyama et al., 1986, Gilfillan and Beaven, 2012). Mast cells isolated from mice and rats are able to take up histamine from the microenvironment (Day and Green, 1962, Cabut and Haegermark, 1966). It has been considered that the uptake of extracellular histamine into bone marrow-derived mast cell granules is mediated by two membrane transporters, vesicular monoamine transporter 2 (VMAT-2), which is expressed on the membrane of exocytotic vesicles, and an unidentified transporter that must be located on the plasma membrane. Because the histamine concentration in the microenvironment around mast cells may reach millimolar levels owing to histamine release, low affinity transporters are assumed to play a role in its uptake via the plasma membrane. Although the mechanism of histamine transport from the cytosol into granules has been elucidated, its uptake from the microenvironment into mast cells and vice versa is still not fully understood. The actions of released monoamine neurotransmitters are terminated by cellular uptake through specific monoamine transporters, such as Na+- and Cl--dependent, high affinity serotonin transporter (SERT), dopamine transporter, and norepinephrine transporter, which is referred to as the uptake-1 system (Huszti, 2003, Perdan-Pirkmajer et al., 2013, Sakurai et al., 2006, Tuomisto and Tuomisto, 1980). In contrast, uptake-2 system transporters, such as bidirectional, Na+- and Cl--independent, and low-affinity-high-capacity transporters, possess numerous characteristics and share a broad range of substrate specificities. These transporters, which are located in the plasma membrane, belong to solute carrier (SLC) 22 and SLC29 families, respectively, and have the ability to transport various organic cations including endogenous biogenic amines and drugs (Grundemann et al., 1999, Engel and Wang, 2005, Duan and Wang, 2010, Koepsell, 2013, Duan et al., 2015). Schneider et al. (2005) showed that murine basophils take up histamine from the microenvironment through organic cation transporter 3 (OCT3). However, there is insufficient data to verify whether histamine uptake by mast cell is also mediated by OCT3.
    Material and methods
    Discussion The release of mediators from mast cells depends on several molecular pathways such as classical exocytotic processes, de novo mediator production, vesicle trafficking and recycling, and exosomal and endosomal pathways. The intracellular resources for histamine release from mast cells include pre-packaged histamine, newly synthesized histamine, and taken up extracellular histamine. The mechanism and contribution of histamine uptake are not well understood, probably because the high level of endogenous histamine present in mast cells usually hampers its uptake. The present study dissected the mechanism of the histamine uptake system and identified possible histamine transporters located on the plasma and vesicle membranes, which may contribute to vesicle recycling and de novo mediator production, and therefore modulate the long term exocytotic ability of mast cells. RBL-2H3 Sc98 cells, a recently identified mutant cell line of RBL-2H3 cells, have a very low histamine content owing to their lack of HDC activity. These cells have become a useful tool to study the mechanism of histamine uptake from extracellular spaces and uptake velocity because of their lack of prepackaged and newly synthesized histamine. The only histamine resource maintained in these cells is acquired by reuptake of extracellular histamine. RBL-2H3 Sc98 cells store histamine taken up from the microenvironment in exocytotic vesicles via VMAT-2. VMAT-2 is essential for the transport and accumulation of monoamines in storage granules (Travis et al., 2000). VMAT-2 recognizes histamine as a substrate and transports it via a mechanism different from that of its other substrates such as catecholamines and indoleamines (Merickel and Edwards, 1995). In IgE-sensitized RBL-2H3 Sc98 cells, the taken up and stored histamine was released from the cells after stimulation with the DNP-BSA antigen. The exocytotic process occurred with concomitant release of β-hexosaminidase, another granule-contained mediator.