Histamine-HisCl1 Receptor Axis Regulates Wake-Promoting Signals in Drosophila melanogaster

Abstract

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.

N‐β‐alanyldopamine metabolism, locomotor activity and sleep in Drosophila melanogaster ebony and tan mutants

“…The different physiological defects shown by ebony 1 and tan 1 demonstrate that NBAD metabolism is more important than previously known for the homeostasis and the normal function of the nervous system. Moreover, NBAD-synthase can metabolize other biogenic amines such as octopamine, tyramine, histamine and 5-HT, which are also involved in the regulation of locomotor activity and sleep in flies (Yuan et al, 2006;Crocker & Sehgal, 2008;Chen et al, 2013;Oh et al, 2013). The NBAD-hydrolase enzyme is also able to hydrolyze other β-alanyl derivatives (True et al, 2005;Pérez et al, 2011).…”

To sleep or not to sleep: neuronal and ecological insights

“…For example, in both mammals and insects, dopaminergic (mammals: [8 •• ,9 •• ]; insects: [10,11]), noradrenergic (mammals: [12]; insects: [13]), and histaminergic (mammals: [14]; insects: [15]) transmissions promote wakefulness, while GABAergic (mammals: [4 • ]; insects: [16,17]) and serotonergic (mammals: [18]; insects: [19]) transmissions promote sleep. This conservation suggests an ancient and common origin for sleep [6].…”

Histidine is selectively required for the growth of Myc‐dependent dedifferentiation tumours in the Drosophila CNS

“…Together, this suggests that the effect of histidine on the growth of nerfin-1 clones is mediated by downstream metabolites 3-methyl-L-histidine and histamine. However, when we knocked down CG3454, encoding a predicted histidine decarboxylase (HDC, RNAi knockdown efficiency previously quantified in Oh et al, 2013) catalysing the conversion of L-histidine into histamine (Hong et al, 2006), we observed a 50% decrease in nerfin-1 but not wildtype clonal volume (Figs 2E and EV3C), which can be partially rescued by supplementation with dietary histamine (Fig EV3D). Together, these results suggest that histamine signalling via its receptor is not required for nerfin-1 clonal growth.…”

“…Together, these results suggest that histamine signalling via its receptor is not required for nerfin-1 clonal growth. However, when we knocked down CG3454, encoding a predicted histidine decarboxylase (HDC, RNAi knockdown efficiency previously quantified in Oh et al, 2013) catalysing the conversion of L-histidine into histamine (Hong et al, 2006), we observed a 50% decrease in nerfin-1 but not wildtype clonal volume (Figs 2E and EV3C), which can be partially rescued by supplementation with dietary histamine (Fig EV3D). Hdc knockdown in nerfin-1 clones decreased clonal volume concomitant with an inhibition of neuron-to-neuroblast reversion, reflected by a drop in the proportion of Deadpan (Dpn + ) NBs and an increase in the proportion of embryonic lethal abnormal vision (Elav + ) neurons per clone ( Fig 2F and G), without significantly impacting on cell death or cell mitoses (Fig EV3E and F).…”

“…Together, this suggests that the effect of histidine on the growth of nerfin-1 clones is mediated by downstream metabolites 3-methyl-L-histidine and histamine. Interestingly, nerfin-1 clone volume was not significantly affected by dietary addition of cimetidine (a histamine receptor inhibitor, Hong et al, 2006) in the adult or knockdown of HisCl1, a histamine receptor in the larvae (RNAi knockdown efficiency previously quantified in Oh et al, 2013; Fig EV3A and B). Together, these results suggest that histamine signalling via its receptor is not required for nerfin-1 clonal growth.…”