GPR156

GPR156 is a constitutively active class C orphan GPCR that couples to Gαi/o proteins to establish mirror-image hair cell orientations in mechanosensory epithelia and modulates neuronal activity in the brain. In the inner ear, EMX2-dependent polarized localization of GPR156 at hair cell junctions activates Gαi signaling to reverse stereociliary bundle orientation relative to the planar cell polarity axis, a process negatively regulated by STK32A; loss of GPR156 causes sensorineural hearing loss and vestibular dysfunction in mice and is linked to hearing loss in humans (PMID:34001891, PMID:37144879, PMID:41547998). Structurally, GPR156 forms a TM5/6-mediated homodimer stabilized by endogenous phospholipid binding within each transmembrane domain, and asymmetric Gα coupling reshapes intracellular loops without disrupting the dimer, explaining high constitutive activity (PMID:38332368, PMID:39638804). A rare missense variant in GPR156 causes medial habenula hyperactivity and stress-related behavioral abnormalities, implicating GPR156 in mood regulation (PMID:40228124).

1. 2003 Medium

   Molecular cloning established GPR156 as a novel class C GPCR related to GABAB receptors, but with no identified ligand or functional signaling partner, defining it as an orphan receptor.

   Evidence Cloning, sequence analysis, and functional expression assays in heterologous cells

   PMID:12591167

   Open questions at the time

   • No ligand identified
   • No signaling output detected in heterologous expression
   • Physiological function unknown
2. 2003 Medium

   Mapping GPR156 protein distribution across the rat CNS revealed expression in cortex, hippocampus, cerebellum, and spinal cord, establishing it as a broadly expressed neuronal receptor.

   Evidence Immunohistochemistry with validated polyclonal antibodies in rat brain sections

   PMID:14556935

   Open questions at the time

   • Single antibody approach without independent validation method
   • Function in any of these brain regions unknown
   • Expression outside CNS not examined
3. 2021 High

   The central biological role of GPR156 was revealed when genetic loss-of-function in mice and zebrafish showed it acts downstream of EMX2 to activate Gαi signaling and reverse hair cell orientation by 180°, solving how mirror-image hair cell patterns are established in mechanosensory organs.

   Evidence Mouse and zebrafish knockouts with epistasis experiments, live imaging of hair cell orientation

   PMID:34001891

   Open questions at the time

   • Mechanism of EMX2-dependent polarized localization unresolved
   • Direct protein-protein interactions mediating pathway not shown
   • Downstream effectors of Gαi in orientation reversal unknown
4. 2021 Medium

   Cell-based signaling assays demonstrated that GPR156 constitutively couples to Gi/o proteins without an exogenous ligand, establishing it as a constitutively active orphan GPCR.

   Evidence Luciferase reporter assay with Gαi/o chimeric G proteins in transfected cells

   PMID:33784795

   Open questions at the time

   • Chimeric G protein assay may not reflect native coupling
   • Single-lab observation at this time point
   • Molecular basis of constitutive activity unknown
5. 2023 High

   Identification of STK32A as a negative regulator of GPR156 apical localization completed the EMX2→STK32A⊣GPR156→Gαi pathway hierarchy for hair cell orientation, explaining how boundary formation between hair cell groups is achieved.

   Evidence Genetic epistasis with double-mutant mice, conditional expression, and immunolocalization

   PMID:37144879

   Open questions at the time

   • Whether STK32A directly phosphorylates GPR156 is not shown
   • Mechanism by which STK32A controls GPR156 apical trafficking unknown
6. 2023 Medium

   A genome-wide CRISPR screen in macrophages revealed an unexpected non-neuronal role: GPR156 drives lipid droplet accumulation downstream of MMGT1, creating a lipid-rich niche that supports Mycobacterium tuberculosis persistence.

   Evidence CRISPR screen in macrophages, KO validation with lipid droplet quantification during Mtb infection

   PMID:37269834

   Open questions at the time

   • Mechanism linking GPR156 signaling to lipid droplet biogenesis unclear
   • Whether Gαi coupling is involved in macrophage context not tested
   • Single study; not independently replicated
7. 2024 High

   Two independent cryo-EM studies resolved the structural basis of GPR156 constitutive activity: the receptor forms a TM5/6-mediated homodimer with endogenous phospholipids bound within each TMD, and asymmetric Gα binding reshapes intracellular loops without disrupting the dimer architecture.

   Evidence Cryo-EM structures in apo, Go-free, Gi3-coupled, and Go-coupled states with functional assays

   PMID:38332368 PMID:39638804

   Open questions at the time

   • Identity of the endogenous phospholipid not definitively assigned
   • Whether phospholipid binding is regulated in vivo unknown
   • No structure of GPR156 in complex with potential allosteric modulators
8. 2024 High

   Electrophysiological and behavioral studies in zebrafish and mouse clarified that GPR156 controls the functional readout of hair cell orientation rather than mechano-electrical transduction itself, as knockout hair cells retain normal transduction properties.

   Evidence Mechano-electrical transduction recordings and behavioral assays in Gpr156 knockout mice and zebrafish

   PMID:39531034

   Open questions at the time

   • How misorientation leads to altered signal integration at the circuit level is unexplored
   • Whether compensatory mechanisms exist in mature animals unknown
9. 2025 High

   Multi-allele epistasis experiments refined the pathway model, establishing that EMX2 represses Stk32a transcription to permit GPR156-mediated bundle reversal, and confirmed GPR156's role is to reverse orientation relative to the PCP axis.

   Evidence Combined Gpr156/Stk32a and Emx2/Stk32a knockout mice with hair cell orientation quantification

   PMID:41208475

   Open questions at the time

   • Direct transcriptional regulation of Stk32a by EMX2 not shown at promoter level
   • Whether additional regulators modulate GPR156 surface expression unknown
10. 2025 High

    A human disease-associated GPR156 missense variant (E533D) knocked into mice caused medial habenula hyperactivity and stress-related behavioral abnormalities, extending GPR156 function beyond the inner ear to mood regulation in the brain.

    Evidence Knock-in mouse with electrophysiology of habenula neurons and behavioral stress assays

    PMID:40228124

    Open questions at the time

    • Mechanism by which E533D alters receptor function (gain vs. loss of activity) not resolved
    • Whether this variant affects Gαi coupling specifically not tested
    • Relevance to human psychiatric phenotypes not clinically validated
11. 2026 High

    Conditional inactivation of Gpr156 specifically in postmitotic hair cells demonstrated that the orientation function is cell-autonomous and confirmed that sensory deficits arise from misorientation rather than impaired transduction.

    Evidence Hair cell-specific conditional knockout with ABR, VOR, and hair cell orientation analysis

    PMID:41547998

    Open questions at the time

    • Whether GPR156 has additional non-cell-autonomous roles in surrounding support cells not excluded
    • Temporal window during which GPR156 acts is not defined

• Key unresolved questions include the identity and regulatory significance of the endogenous phospholipid bound within the GPR156 dimer, the downstream effectors of Gαi that execute cytoskeletal remodeling for bundle reversal, whether STK32A directly phosphorylates GPR156, and the mechanism by which GPR156 promotes lipid droplet formation in macrophages.
• No substrate/effector downstream of Gαi in hair cells identified
• Phospholipid identity and regulation unresolved
• STK32A-GPR156 direct interaction not demonstrated
• Macrophage signaling mechanism unexplored