Advances in GPCRs Associated With Wnt Signaling Within the Auditory System

ABSTRACT G protein‐coupled receptors (GPCRs) that interact with the Wnt signaling pathway are pivotal for auditory system homeostasis, as they orchestrate inner ear development, hair cell (HC) regeneration, and hearing preservation. Frizzled (FZD) receptors, the core Wnt‐related GPCRs, bind Wnt ligands and co‐receptors (e.g., LRP5/6) to activate both canonical β‐catenin–dependent signaling and noncanonical cascades (Wnt/Ca 2+ and planar cell polarity [PCP]), thereby governing cochlear morphogenesis via regulating cell proliferation, differentiation, and PCP. Leucine‐rich repeat‐containing GPCRs (LGR4/5/6) further amplify Wnt signaling: By binding R‐spondins, they inhibit E3 ubiquitin ligases RNF43/ZNRF3 (which promote FZD degradation), stabilizing membrane‐localized FZD, enhancing receptor clustering, and sustaining stem cell pluripotency critical for HC regeneration. Targeting these Wnt‐associated GPCRs has been shown to boost the regenerative capacity of cochlear progenitor cells via Wnt modulation. Furthermore, mutations in GPCRs can lead to hearing impairment. For example, the GPR156 mutation causes autosomal recessive congenital hearing loss, indicating that GPCRs can serve as a target for the treatment of hearing loss. This review systematically clarifies how Wnt‐associated GPCRs regulate cochlear development and highlights their unique value in developing therapies for hearing restoration and preservation.