Drosophila Vision Depends on Carcinine Uptake by an Organic Cation Transporter

Abstract

Recycling of neurotransmitters is essential for sustained neuronal signaling, yet recycling pathways for various transmitters, including histamine, remain poorly understood. In the first visual ganglion (lamina) of Drosophila, photoreceptor-released histamine is taken up into perisynaptic glia, converted to carcinine, and delivered back to the photoreceptor for histamine regeneration. Here, identify an organic cation transporter, CarT (carcinine transporter), that transports carcinine into photoreceptors during histamine recycling. CarT mediated in vitro uptake of carcinine. Deletion of the CarT gene caused an accumulation of carcinine in laminar glia accompanied by a reduction in histamine, resulting in abolished photoreceptor signal transmission and blindness in behavioral assays. These defects were rescued by expression of CarT cDNA in photoreceptors, and were reproduced by photoreceptor-specific CarT knockdown. Our findings suggest a common role for the conserved family of CarT-like transporters in maintaining histamine homeostasis in both mammalian and fly brains.

LOVIT Is a Putative Vesicular Histamine Transporter Required in Drosophila for Vision

“…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).…”

“…Histamine in the synaptic cleft is quickly taken up into epithelial glia and inactivated to carcinine by Ebony, which catalyzes the conjugation of histamine and b-alanine (Borycz et al, 2002). Carcinine is subsequently transported back to PRs via CarT (Chaturvedi et al, 2016;Stenesen et al, 2015;Xu et al, 2015), After being deconjugated from carcinine by Tan in the PRs, histamine is repackaged into synaptic vesicles through LOVIT to maintain the neurotransmitter pool for vesicular release.…”

Two Novel Forms of ERG Oscillation inDrosophila: Age and Activity Dependence

“…Although the precise physiological mechanisms by which rosA mutations induce RP oscillations remain unclear (Gavin et al ., 2007), the rosA gene product along with other neurotransmitter transporters (e.g. carT , see Xu et al , 2015; Chaturvedi et al ., 2016) may play an important role in shuttling histamine and related metabolites across the plasma membranes of photoreceptors and surrounding glia in the visual system—a potentially important mechanism in generating ERG waveform oscillations.…”

The β-alanine transporter BalaT is required for visual neurotransmission in Drosophila

“…Histamine is inactivated when Ebony catalyzes its conjugation to β-alanine in laminar glial cells ( Borycz et al, 2002 ; Richardt et al, 2002 ). In photoreceptors, CarT and Tan are involved in transporting carcinine and regenerating histamine, respectively ( Chaturvedi et al, 2016 ; Stenesen et al, 2015 ; Wagner et al, 2007 ; Xu et al, 2015 ). Histamine is then loaded into synaptic vesicles, but fate of the β-alanine generated by Tan remains unknown.…”

“…In these laminar glia, histamine is conjugated to β-alanine by an N-β-alanyl-dopamine synthase, called Ebony, to form the inactive metabolite, carcinine ( Borycz et al, 2002 ; Richardt et al, 2003 , 2002 ). Recently, a carcinine transporter, CarT that is responsible for the uptake of carcinine from the synaptic cleft into photoreceptors has been identified ( Chaturvedi et al, 2016 ; Stenesen et al, 2015 ; Xu et al, 2015 ). The discovery that CarT retrieves carcinine directly from the laminar synaptic cleft indicates that carcinine is not transported from laminar glia to photoreceptor cell bodies through a long-distance trafficking mechanism involving the laminar glial and pigment cell network.…”