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  • Introduction Histamine was generally accepted as a neurotran

    2022-08-02

    Introduction Histamine was generally accepted as a neurotransmitter in 1984, when histamine was first identified to be located in tuberomamillary nucleus (TM) of the brain (Watanabe et al., 1984). In mammals, histaminergic neurons play an important role in regulating multiple physiological activities, including sleep, synaptic plasticity, and feeding behaviors (Bekkers, 1993, Huang et al., 2001, Parmentier et al., 2002, Vorobjev et al., 1993). Deregulation of histaminergic neurotransmission can lead to several neurologic disorders, such as schizophrenia and multiple sclerosis (Haas and Panula, 2003). In various adult arthropods, from crustaceans to insects, photoreceptors use histamine as the main neurotransmitter to deliver visual signals (Stuart, 1999). Despite its importance as a neurotransmitter, histaminergic neurotransmission is not well understood. Vesicular neurotransmitter transporters in synaptic vesicles are required to load, release, and recycle their corresponding neurotransmitters. Four major vesicular transporters—VGLUT (vesicular glutamate transporter), VGAT (vesicular GABA transporter), VAChT (vesicular Sodium Nitroprusside australia transporter), and VMAT (vesicular monoamine transporter)—contribute to the synaptic concentration of glutamate, gamma-aminobutyric acid (GABA), acetylcholine, and monoamines, respectively (Alfonso et al., 1993, Erickson et al., 1996, Fremeau et al., 2001, McIntire et al., 1993). In mammals, both VMAT1 and VMAT2 mediate vesicular transport of most monoamines, including serotonin, dopamine, and histamine, whereas VMAT2, not VMAT1, is primarily responsible for histamine vesicular uptake in the CNS (Haas and Panula, 2003, Peter et al., 1995). However, some histamine-positive neurons lack VMAT2, suggesting that another vesicular transporter for histamine may exist (Kukko-Lukjanov and Panula, 2003). In Drosophila, VMAT is absent in photoreceptor cells, which use histamine as their primary neurotransmitter, leading us to speculate that an unknown transporter is responsible for the vesicular transport of histamine (Romero-Calderón et al., 2008). Here, we demonstrated that a previously uncharacterized Drosophila gene CG45782, called lovit, encodes a photoreceptor-specific synaptic vesicular transporter responsible for concentrating histamine at synapses and that its activity is required to transmit visual signals.
    Results
    Discussion Most neurons communicate at synapses through the release of neurotransmitters. Classical neurotransmitters are synthesized in the cytoplasm and must be transported into synaptic vesicles before being released. In mammals, histamine is transported into synaptic vesicles by the VMAT family of transporters. After a light stimulus, Drosophila photoreceptor cells use histamine as major neurotransmitter to trigger signaling of downstream neurons. However, the single Drosophila ortholog to VMAT, dVMAT, is absent in photoreceptors. Another vesicular transporter that loads histamine into synaptic vesicles must therefore exist in photoreceptors. Using a genetic approach to identify the transporters required for visual transmission in Drosophila photoreceptors, we characterized a new putative vesicular transporter, LOVIT, required to concentrate histamine in photoreceptor terminals. LOVIT is concentrated in photoreceptor synaptic vesicles and is necessary and sufficient to maintain normal visual transmission and phototactic behaviors. Because we could not express LOVIT in vitro (data not shown), which might be due to the strict quality control of photoreceptor-cell-specific membrane proteins (Wang and Montell, 2007), direct histamine transporting activity could not be demonstrated through a biochemistry assay. However, loss of LOVIT significantly disrupted the histamine concentration in synaptic vesicles, suggesting that LOVIT functions as a putative vesicular histamine transporter in vivo. Another possibility is that LOVIT may not directly transport histamine, but its substrate is a necessary cofactor for histamine transportation. However, the second hypothesis is relatively weak: LOVIT is the only photoreceptor-enriched transporter candidate beside the CarT transporter.