This article reviews and presents new data regarding the nicotinic acetylcholine receptor subunits α9 and α10. Although phylogentically ancient, these subunits have only recently been identified as critical components of the efferent auditory system and medial olivocochlear pathway. This pathway is important in auditory processing by modulating outer hair cell function to broadly tune the cochlea and improve signal detection in noise. Pharmacologic properties of the functionally expressed α9α10 receptor closely resemble the cholinergic response of outer hair cells. Molecular, immunohistochemical, and knockout mice studies have added further weight to the role this receptor plays in mediating the efferent auditory response. Alternate and complementary mechanisms of outer hair cell efferent activity might also be mediated through the nAChR α9α10, either through secondary calcium stores, second messengers, or direct protein-protein interactions. We investigated protein-protein interactions using a yeast-two-hybrid screen of the nAChR α10 intracellular loop against a rat cochlear cDNA library. Among the identified proteins was prosaposin, a precursor of saposins, which have been shown to act as neurotrophic factors in culture, can bind to a putative G0-coupled cell surface receptor, and may be involved in the prevention of cell death. This study and review suggest that nAChR α9α10 may represent a potential therapeutic target for a variety of ear disorders, including preventing or treating noise-induced hearing loss, or such debilitating disorders as vertigo or tinnitus. Anat Rec Part A, 2006. © 2006 Wiley-Liss, Inc.