An evolutionarily conserved cation channel tunes the sensitivity of gustatory neurons to ephaptic inhibition in Drosophila

In ephaptic coupling, physically adjacent neurons influence one another's activity via the electric fields they generate. To date, the molecular mechanisms that mediate and modulate ephaptic coupling's effects remain poorly understood. Here, we show that the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel lateralizes the potentially mutual ephaptic inhibition between Drosophila gustatory receptor neurons (GRNs). While sweet-sensing GRNs (sGRNs) engage in ephaptic suppression of the adjacent bitter-sensing GRNs (bGRNs), HCN expression in sGRNs enables them to resist ephaptic suppression from the bGRNs. This one-sided ephaptic inhibition confers sweetness dominance, facilitating ingestion of bitter-laced sweets. The role of fly HCN in this process can be replaced by human HCN2. Furthermore, unlike the mechanism in olfaction, gustatory ephaptic inhibition is independent of sensillum potential changes, suggesting that the compartmentalized arrangement of neighboring GRNs is dispensable for gustatory ephaptic inhibition. These findings indicate a role for the gating of ephaptic coding to ensure the intake of the essential nutrient despite bitter contaminants present in the feeding niche of Drosophila, and propose that studies in Drosophila gustation could reveal ephaptic principles conserved across diverse animals.