Drosophila SLC5A11 Mediates Hunger by Regulating K + Channel Activity

Abstract

SUMMARY Hunger is a powerful drive that stimulates food intake. Yet the mechanism that determines how the energy deficits that result in hunger are represented in the brain and promote feeding is not well understood. We previously described SLC5A11 – a sodium/solute co-transporter-like – (or cupcake) in Drosophila melanogaster, which is required for the fly to select a nutritive sugar over a sweeter nonnutritive sweetener after periods of food deprivation. SLC5A11 acts on approximately 12 pairs of ellipsoid body (EB) R4 neurons to trigger the selection of nutritive sugars, but the underlying mechanism is not understood. Here, we report that the excitability of SLC5A11-expressing EB R4 neurons increases dramatically during starvation and that this increase is abolished in the SLC5A11 mutation. Artificial activation of SLC5A11-expresssing neurons is sufficient to promote feeding and hunger-driven behaviors; silencing these neurons has the opposite effect. Notably, SLC5A11 transcript levels in the brain rose significantly when flies were starved, and dropped shortly after starved flies were refed. Furthermore, expression of SLC5A11 is sufficient for promoting hunger-driven behaviors and enhancing the excitability of SLC5A11-expressing neurons. SLC5A11 inhibits the function of Drosophila KCNQ potassium channel in a heterologous expression system. Accordingly, a knock-down of dKCNQ expression in SLC5A11-expressing neurons produces hunger-driven behaviors even in fed flies, mimicking the overexpression of SLC5A11. We propose that starvation increases SLC5A11 expression, which enhances the excitability of SLC5A11-expressing neurons by suppressing dKCNQ channels, thereby conferring the hunger state.

KCNQ‐SMIT complex formation facilitates ion channel‐solute transporter cross talk

“…In addition, KCNQ‐SLC5A11 complex formation has also been reported in Drosophila, where up‐regulation or overexpression of the Drosophila sodium/solute cotransporter‐like SLC5A11 (aka cupcake ) causes marked reductions in Drosophila (d) KCNQ expression and macroscopic current. dKCNQ, an ortholog of mammalian KCNQ family α subunits, possesses some characteristics reminiscent of KCNQ1 and some of KCNQ2 (27). Similar to our prior findings for mammalian SLC5A11 (SMIT2) and KCNQ1 (8), cupcake inhibits dKCNQ activity, even though it has yet to be demonstrated that cupcake acts as a sugar or cyclic polyol transporter [it does pass sodium‐dependent constitutive current, but does not pass glucose‐dependent current (27)].…”

Taotie neurons regulate appetite in Drosophila

“…Another neurotransmitter, octopamine, is crucial for starvation-induced hyperactivity, but not required for the regulation of energy intake during starvation56. Recent studies indicated that a subset of serotonergic neurons, the R4 neurons in ellipsoid body and four neurons in SEZ, participate in hunger sensation in Drosophila 216566. How much these circuits contribute to various aspects of hunger sensation, especially how they interact dynamically and collectively to control feeding, remains to be revealed.…”

Chansporter complexes in cell signaling

“…However, as described for mammalian SMITs above, cupcake coassembles with dKCNQ, a Drosophila Kv channel orthologous to mammalian KCNQs. Cupcake coassembly inhibits dKCNQ (as we previously found for the mammalian cupcake ortholog, SMIT2, with KCNQ1 ), and dKCNQ is required for normal feeding behavior and food selection by controlling the excitability of neurons expressing cupcake .…”

“…In the case of K ATP channels, although SURs do not possess transport machinery, they sense the metabolic state of the cell and report this to the Kir6 channels to regulate their function . Likewise, cupcake may not possess sugar transport capabilities, but it is suggested to sense sugar levels and it is possible that via coassembly, it can communicate these to dKCNQ to regulate feeding behavior.…”

“…Thus, unlike related mammalian transporters such as SGLT1, cupcake lacks a consensus sugar‐binding site. Cupcake does not generate glucose‐dependent currents when it is studied in Xenopus oocytes, although it does pass a large constitutive current that requires sodium and a conserved sodium‐binding site . However, as described for mammalian SMITs above, cupcake coassembles with dKCNQ, a Drosophila Kv channel orthologous to mammalian KCNQs.…”