Stereocilia are microvilli-like structures that protrude from the apical surface of certain types of sensory cells, such as hair cells in the inner ear and photoreceptor cells in the retina. The stereocilia membrane is a specialized membrane that covers the stereocilia and is involved in sensory transduction. The stereocilia membrane contains various types of ion channels, transporters, and scaffolding proteins that mediate the flow of ions and other molecules, such as neurotransmitters, between the extracellular and intracellular compartments. The stereocilia membrane is also organized in a unique way, with different ion channels and transporters being localized to specific regions of the stereocilia, which is critical for the proper functioning of the sensory cells.

LHFPL5 stands for Lipoma HMGIC Fusion Partner-Like 5, which is a gene that codes for a protein that is a component of the hair cell stereocilia in the inner ear. Mutations in the LHFPL5 gene have been linked to hearing loss, particularly in high frequencies.

The mechano-electrical transduction (MET) channel of the inner ear receptor cells, termed hair cells, is a protein complex that enables our senses of hearing and balance. Hair cell MET requires an elaborate interplay of multiple proteins that form the MET channel. One of the MET complex components is the transmembrane protein LHFPL5, which is required for hair cell MET and hearing. LHFPL5 is thought to form a multi-protein complex with other MET channel proteins, such as PCDH15, TMIE, and TMC1. Despite localizing to the plasma membrane of stereocilia, the mechanosensing organelles of hair cells, LHFPL5 requires its binding partner within the MET complex, PCDH15, to localize to the stereocilia tips in hair cells and to the plasma membrane in heterologous cells. Using the Aquaporin 3-tGFP reporter (AGR) for plasma membrane localization, Soler et al from the University Hospitals Cleveland Medical Center, found that a region within extracellular loop 1, which interacts with PCDH15, precludes the trafficking of AGR reporter to the plasma membrane in heterologous cell lines. The results suggest that the presence of protein partners may mask endoplasmic reticulum retention regions or enable the proper folding and trafficking of the MET complex components, to facilitate the expression of the MET complex at the stereocilia membrane ¹⁾.