Histamine-HisCl1 receptor axis regulates wake-promoting signals in Drosophila melanogaster

PLoS One. 2013 Jul 3;8(7):e68269. doi: 10.1371/journal.pone.0068269. Print 2013.


Histamine and its two receptors, histamine-gated chloride channel subunit 1 (HisCl1) and ora transientless (Ort), are known to control photoreception and temperature sensing in Drosophila. However, histamine signaling in the context of neural circuitry for sleep-wake behaviors has not yet been examined in detail. Here, we obtained mutant flies with compromised or enhanced histamine signaling and tested their baseline sleep. Hypomorphic mutations in histidine decarboxylase (HDC), an enzyme catalyzing the conversion from histidine to histamine, caused an increase in sleep duration. Interestingly, hisCl1 mutants but not ort mutants showed long-sleep phenotypes similar to those in hdc mutants. Increased sleep duration in hisCl1 mutants was rescued by overexpressing hisCl1 in circadian pacemaker neurons expressing a neuropeptide pigment dispersing factor (PDF). Consistently, RNA interference (RNAi)-mediated depletion of hisCl1 in PDF neurons was sufficient to mimic hisCl1 mutant phenotypes, suggesting that PDF neurons are crucial for sleep regulation by the histamine-HisCl1 signaling. Finally, either hisCl1 mutation or genetic ablation of PDF neurons dampened wake-promoting effects of elevated histamine signaling via direct histamine administration. Taken together, these data clearly demonstrate that the histamine-HisCl1 receptor axis can activate and maintain the wake state in Drosophila and that wake-activating signals may travel via the PDF neurons.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chloride Channels / metabolism*
  • Dose-Response Relationship, Drug
  • Drosophila Proteins / deficiency
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / metabolism*
  • Female
  • Histamine / metabolism
  • Histamine / pharmacology
  • Male
  • Mutation
  • Neurons / drug effects
  • Neurons / metabolism
  • Neuropeptides / metabolism
  • Phenotype
  • Signal Transduction* / drug effects
  • Sleep / drug effects
  • Sleep / genetics
  • Wakefulness / drug effects
  • Wakefulness / physiology*


  • Chloride Channels
  • Drosophila Proteins
  • Hdc protein, Drosophila
  • Neuropeptides
  • ort protein, Drosophila
  • pdf protein, Drosophila
  • Histamine

Grant support

This work was supported by grants from the Brain Research Center of the 21st Century Frontier Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (MEST), the Republic of Korea, and from the National Research Foundation of Korea grant funded by MEST (No. 20110015442). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.