GPR156 is a class C orphan G protein-coupled receptor essential for auditory and vestibular function. Its primary role is regulating hair cell orientation in the inner ear by triggering a 180-degree reversal in stereociliary bundle orientation, creating a line of polarity reversal (LPR) across sensory organs 1. Mechanistically, GPR156 exhibits constitutive activity through a unique mechanism lacking a large extracellular domain 2. High constitutive activity is maintained through homodimeric TM5/6-TM5/6 interface formation, with endogenous phospholipid molecules within transmembrane domains serving as transducers for sustained G protein (Gi/o) signaling 32. In hair cells expressing EMX2, GPR156 is apically enriched at cell junctions and reverses core planar cell polarity interpretation 1. Loss-of-function variants in GPR156 cause autosomal recessive congenital hearing impairment and non-syndromic moderate sensorineural hearing loss 45. Conditional hair cell-specific GPR156 inactivation recapitulates cochlear and utricular misorientation with auditory and vestibular dysfunction, demonstrating that sensory deficits primarily result from impaired hair cell orientation 1. Additionally, a rare missense variant (c.1599G>T, p.Glu533Asp) in GPR156 is associated with increased major depressive disorder risk in founder populations, implicating GPR156 in mood regulation through medial habenula function 6.