GPR151

GPR151 is an orphan Gαi-coupled GPCR enriched in habenular neurons and nociceptive dorsal root ganglion (DRG) neurons that functions as a proton sensor and modulator of pain-related neuroinflammatory signaling. It is activated by extracellular acidification (optimal ~pH 5.8), couples exclusively to Gαi, and signals through Gβγ to activate ERK and downstream chemokines (CCL5, CCL7, CXCL9, CXCL10), while physically associating with P2X3 ion channels to potentiate their calcium-conductance activity and drive CSF1-dependent spinal microglial activation after nerve injury (PMID:31119277, PMID:33239523, PMID:34244727). In the habenula, GPR151 is expressed in cholinergic and glutamatergic projection neurons innervating midbrain targets, and its deletion impairs social reward behavior (PMID:25116430, PMID:36424418).

1. 2014 Medium

   Establishing where GPR151 protein is expressed resolved that this orphan receptor is a habenula-specific marker whose axonal projections reach defined midbrain nuclei, framing it as a potential regulator of habenular circuit function.

   Evidence Immunohistochemistry and confocal colocalization in rat, mouse, and zebrafish brain sections

   PMID:25116430

   Open questions at the time

   • No functional consequence of habenular GPR151 expression was demonstrated
   • Expression in peripheral sensory neurons was not examined in this study
2. 2016 Medium

   Despite sequence homology with galanin receptors, galanin was excluded as a GPR151 ligand, clarifying that the receptor remains an orphan GPCR with an unknown endogenous agonist.

   Evidence Calcium signaling assay in GPR151-transfected ND7/23 cells with galanin

   PMID:27913310

   Open questions at the time

   • Only one candidate ligand was tested; no systematic ligand screen was performed
   • Assay relied on calcium readout, which may miss Gαi-coupled responses
3. 2019 Medium

   Identification of extracellular protons as GPR151 activators solved the receptor's activation stimulus, establishing it as a pH-sensing GPCR coupled to Gi signaling with maximal activity around pH 5.8.

   Evidence [35S]GTPγS binding assay with GPR151-Gαi fusion proteins and CHO cell reporter gene assay at varying pH

   PMID:31119277

   Open questions at the time

   • Proton activation demonstrated only in heterologous systems; not confirmed in native neurons
   • Whether protons are the sole or primary endogenous stimulus is unresolved
4. 2021 High

   Defining the GPR151 signaling cascade in sensory neurons — Gαi coupling, Gβγ-ERK activation, and downstream neuroinflammatory chemokine induction — established the intracellular pathway by which this receptor drives neuroinflammation after nerve injury.

   Evidence Co-IP with Gα subunits, phospho-ERK staining, MEK inhibitor blockade, gene microarray in Gpr151-/- mice after partial infraorbital nerve transection

   PMID:33239523

   Open questions at the time

   • Whether the Gβγ-ERK axis operates identically in DRG versus trigeminal neurons is untested
   • Direct identification of the kinase linking Gβγ to ERK was not performed
5. 2021 High

   Demonstrating that GPR151 physically couples to P2X3 channels and is required for CSF1-dependent microglial activation placed GPR151 at the apex of a nociceptive signaling cascade (GPR151→P2X3→CSF1→microglia), explaining its role in neuropathic pain.

   Evidence Co-IP, calcium imaging, conditional KO and overexpression in DRG neurons, P2X3 siRNA, microglial marker immunohistochemistry in chronic constriction injury model

   PMID:34244727

   Open questions at the time

   • Structural basis of the GPR151–P2X3 physical interaction is unknown
   • Whether GPR151 modulates other ion channels beyond P2X3 has not been tested
6. 2022 Medium

   GPR151 knockout reduced social preference behavior, extending the receptor's functional roles beyond pain into habenula-dependent social reward processing.

   Evidence Social preference test in Gpr151-/- versus wild-type mice

   PMID:36424418

   Open questions at the time

   • Circuit-level mechanism (which habenular projection mediates the effect) is unresolved
   • Rescue experiments restoring GPR151 selectively in habenula were not performed
7. 2022 Medium

   Functional validation of human GPR151 loss-of-function variants and metabolic phenotyping of Gpr151-/- mice showed that GPR151 deficiency increases body weight on high-fat diet, linking the receptor to metabolic regulation under dietary stress.

   Evidence In vitro functional assays for human LOF variants; body weight measurements on normal and high-fat diet in Gpr151-/- mice

   PMID:35381001

   Open questions at the time

   • Mechanism connecting GPR151 loss to high-fat diet weight gain is unknown
   • Whether the metabolic phenotype is habenula-dependent or peripheral is untested

• The endogenous lipid or peptide ligand (if any, beyond protons) of GPR151, the structural basis of its P2X3 interaction, and the neural circuit mechanisms underlying its roles in social behavior and metabolism remain unresolved.
• No endogenous non-proton ligand has been identified
• No structural or cryo-EM model of GPR151 or the GPR151–P2X3 complex exists
• Cell-type-specific rescue or chemogenetic studies in habenula are lacking