Structural basis of PSCC1 in Drosophila melanogaster: A neurotransmitter-independent pLGIC.

The pentameric ligand-gated ion channel (pLGIC) superfamily is widely distributed across diverse organisms, ranging from prokaryotic environmental sensors to vertebrate neurotransmitter-gated receptors that mediate rapid synaptic transmission. However, high-resolution structural information on invertebrate pLGICs remains limited, which hinders mechanistic understanding of their architecture, ligand-independent gating, and functional diversity. The pH-sensitive chloride channel 1 (PSCC1) is a neurotransmitter-independent pLGIC activated by alkaline pH, which plays essential roles in osmotic balance and growth regulation in insects. Here, we report the cryo-EM structure of Drosophila melanogaster PSCC1 in a resting state at 3.04 Å resolution. PSCC1 exhibits a canonical pentameric architecture with a conserved β-sandwich fold in the ECD, but displays a drastically altered neurotransmitter-binding pocket, accounting for its ligand-independent gating mechanism. Comparative structural analyses with prokaryotic and vertebrate pLGICs reveal distinct structural features in both the ECD and TMD of PSCC1, highlighting its unique architecture within the pLGIC superfamily. Our findings suggest the molecular basis of PSCC1 function in insect physiology and provide a structural framework for understanding the molecular diversity of non-canonical invertebrate pLGICs.