module: dmel_histamine_metabolism
title: Histamine synthesis and recycling in Drosophila melanogaster
label: Histamine metabolism
module_type: METABOLIC_PATHWAY
description: >-
  Histamine is the neurotransmitter of Drosophila photoreceptors and some
  central neurons. Histidine decarboxylase (Hdc) makes histamine from
  histidine, and LOVIT, a putative vesicular histamine transporter, maintains
  histamine in photoreceptor synaptic terminals. After release, histamine is
  taken up by surrounding epithelial glia, in part by the histamine-specific
  transporter HisT. In glia, Ebony conjugates histamine with beta-alanine to
  form carcinine (beta-alanyl-histamine), which returns to photoreceptors
  through the carcinine transporter CarT. Tan then hydrolyses carcinine,
  releasing histamine for reuse. This glia-photoreceptor recycling loop
  sustains visual transmission when de novo synthesis is limiting.
summary: >-
  Histamine synthesis by Hdc, vesicular storage by LOVIT and glial recycling
  through HisT, Ebony, CarT and Tan.
concepts:
  - {id: GO:0001692, label: histamine metabolic process}
parts:
  - id: histamine_synthesis
    label: Histamine synthesis
    role: histidine to histamine in photoreceptors
    genes: [Hdc]
    function: {id: GO:0004398, label: histidine decarboxylase activity}
  - id: vesicular_histamine_loading
    label: Vesicular histamine storage
    role: maintaining synaptic histamine in photoreceptor terminals
    description: >-
      LOVIT is an SLC45 protein on photoreceptor synaptic vesicles; its
      transport activity has not been shown directly.
    genes: [lovit]
  - id: glial_histamine_uptake
    label: Glial histamine uptake
    role: histamine uptake into epithelial glia
    genes: [HisT]
    function: {id: GO:0160173, label: histamine transmembrane transporter activity}
  - id: carcinine_synthesis
    label: Carcinine synthesis
    role: histamine + beta-alanine to carcinine in glia
    genes: [e]
    function: {id: GO:0003833, label: beta-alanyl amine synthase activity}
  - id: carcinine_transport
    label: Carcinine uptake into photoreceptors
    role: carcinine import into photoreceptors
    genes: [CarT]
    function: {id: GO:1905131, label: carcinine transmembrane transporter activity}
  - id: carcinine_hydrolysis
    label: Carcinine hydrolysis
    role: carcinine to histamine + beta-alanine in photoreceptors
    genes: [t]
    function: {id: GO:0031964, label: beta-alanyl-histamine hydrolase activity}
connections:
  - source: histamine_synthesis
    target: vesicular_histamine_loading
    connection_type: PRECEDES
    description: Newly made histamine is stored in synaptic vesicles.
  - source: vesicular_histamine_loading
    target: glial_histamine_uptake
    connection_type: PRECEDES
    description: Released histamine is cleared from the synapse into glia.
  - source: glial_histamine_uptake
    target: carcinine_synthesis
    connection_type: PRECEDES
    description: Glial histamine is conjugated to beta-alanine by Ebony.
  - source: carcinine_synthesis
    target: carcinine_transport
    connection_type: PRECEDES
    description: Carcinine returns from glia to photoreceptors through CarT.
  - source: carcinine_transport
    target: carcinine_hydrolysis
    connection_type: PRECEDES
    description: Tan hydrolyses carcinine in photoreceptors.
  - source: carcinine_hydrolysis
    target: vesicular_histamine_loading
    connection_type: PROVIDES_INPUT_FOR
    description: Recycled histamine is reloaded into synaptic vesicles.
knowledge_gaps:
  - gap_statement: >-
      Which transporter carries histamine from the synaptic cleft into glia
      besides HisT, how carcinine leaves glia, and whether LOVIT itself
      transports histamine into vesicles are not known.
    boundary: Transport steps of the histamine recycling loop.
    gap_kind: [BIOLOGY]
notes: >-
  Boundary. The module covers the six FlyBase members. Ebony and Tan also act
  in cuticle tanning (on dopamine rather than histamine) and appear in that
  module as well. Histamine receptors (HisCl1, ort) are downstream of the
  module.
evidence:
  - source_id: PMID:36288320
    title: Drosophila HisT is a specific histamine transporter that contributes to histamine recycling in glia.
    statement: Identifies HisT as a glial histamine-specific transporter that contributes to histamine recycling.
    supporting_text: >-
      we identified an epithelial glia-expressing transporter, HisT (Histamine
      Transporter), that specifically transports histamine into cells.
  - source_id: PMID:31042461
    title: LOVIT Is a Putative Vesicular Histamine Transporter Required in Drosophila for Vision.
    statement: Identifies LOVIT on photoreceptor synaptic vesicles and shows it is needed for synaptic histamine.
    supporting_text: >-
      LOVIT is prominently expressed in photoreceptor synaptic vesicles and is
      required for Drosophila visual neurotransmission.
group: HISMET