Histamine Recycling Is Mediated by CarT, a Carcinine Transporter in <i>Drosophila</i> Photoreceptors

<div><p>Histamine is an important chemical messenger that regulates multiple physiological processes in both vertebrate and invertebrate animals. Even so, how glial cells and neurons recycle histamine remains to be elucidated. <i>Drosophila</i> photoreceptor neurons use histamine as a neurotransmitter, and the released histamine is recycled through neighboring glia, where it is conjugated to β-alanine to form carcinine. However, how carcinine is then returned to the photoreceptor remains unclear. In an mRNA-seq screen for photoreceptor cell-enriched transporters, we identified CG9317, an SLC22 transporter family protein, and named it CarT (<u>Car</u>cinine <u>T</u>ransporter). S2 cells that express CarT are able to take up carcinine <i>in vitro</i>. In the compound eye, CarT is exclusively localized to photoreceptor terminals. Null mutations of <i>cart</i> alter the content of histamine and its metabolites. Moreover, null <i>cart</i> mutants are defective in photoreceptor synaptic transmission and lack phototaxis. These findings reveal that CarT is required for histamine recycling at histaminergic photoreceptors and provide evidence for a CarT-dependent neurotransmitter trafficking pathway between glial cells and photoreceptor terminals.</p>