Affinage

HCAR1

Hydroxycarboxylic acid receptor 1 · UniProt Q9BXC0

Length
346 aa
Mass
39.3 kDa
Annotated
2026-06-10
51 papers in source corpus 29 papers cited in narrative 29 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HCAR1 (GPR81) is a class A Gαi/o-coupled G protein-coupled receptor that functions as the principal sensor of extracellular L-lactate, transducing metabolic state into cellular signaling across the brain, vasculature, reproductive tract, kidney, gut, and tumor microenvironment (PMID:30926749, PMID:28534495, PMID:27615440). Cryo-EM structures of the HCAR1-Gi1 complex reveal a compact orthosteric pocket stabilized by unique disulfide bonds; L-lactate binds weakly (requiring millimolar concentrations) while synthetic agonists such as CHBA engage more stably, and self-activation is driven by an extracellular loop 2 rearrangement with Phe168 acting as an intrinsic agonist (PMID:40233099, PMID:41493973). The receptor preferentially activates Gαi/o (and Gαs) with minimal β-arrestin recruitment, suppressing the adenylyl cyclase–cAMP–PKA axis while liberating Gβγ subunits (PMID:41435849, PMID:30926749). Through these effectors HCAR1 downmodulates neuronal excitability and synaptic transmission—decreasing miniature EPSC frequency presynaptically and hyperpolarizing neurons via Gβγ-dependent GIRK channel opening—such that HCAR1-deficient mice display lowered seizure thresholds and increased seizure burden (PMID:30926749, PMID:35240875, PMID:31755997, PMID:38655197). In the cerebral vasculature, lactate-driven HCAR1 activation in pial fibroblasts and pericytes raises VEGFA and capillary density to promote angiogenesis, and it stimulates neurogenesis and tissue regeneration in the ventricular-subventricular zone (PMID:28534495, PMID:33244894, PMID:35942676). HCAR1 also acts as an anti-inflammatory and metabolic regulator: it suppresses IL-1β-induced proinflammatory gene transcription in myometrium (PMID:27615440), regulates adipocyte lipid accumulation and podocyte lipolysis through the cAMP/PKA-ATGL axis (PMID:23268337, PMID:39962919), and in astrocytes triggers Ca2+ signaling and glutamate release that tunes hypothalamic POMC neuron excitability (PMID:41945430). In cancer, HCAR1 promotes ferroptosis resistance via an AMPK–SREBP1–SCD1 axis in hepatocellular carcinoma (PMID:33296645), recruits immunosuppressive CCR2+ PMN-MDSCs through CCL2/CCL7 induction in colorectal tumors (PMID:39905201), and drives osteosarcoma progression via β-arrestin2/PP2A-mediated STAT1/2 dephosphorylation (PMID:40956299).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2012 Medium

    Establishing that naturally occurring HCA1 variants alter receptor function and that HCA1 governs adipocyte lipid homeostasis answered whether this orphan-like receptor has a defined physiological role in metabolism.

    Evidence Luciferase reporter assays of missense variants in HEK293 cells plus siRNA knockdown in differentiating OP9 adipocytes

    PMID:23268337

    Open questions at the time
    • Ligand identity and signaling mechanism not dissected here
    • Variant effects on in vivo metabolism not tested
    • Single lab
  2. 2016 High

    Showing that lactate-GPR81 signaling suppresses proinflammatory gene transcription in myometrium established the receptor as an anti-inflammatory effector with reproductive consequences.

    Evidence Primary myometrial smooth muscle cell culture, ex vivo uteri, shRNA knockdown, GPR81 KO mice, and an endotoxin-induced preterm birth model

    PMID:27615440

    Open questions at the time
    • Downstream signaling effectors not fully mapped
    • Chemokine targets identified only later in other tissues
  3. 2017 High

    Localizing HCAR1 to pial fibroblasts and pericytes and demonstrating lactate-dependent VEGFA induction answered how exercise/lactate drives cerebral angiogenesis through this receptor.

    Evidence Immunohistochemistry, HCAR1 KO mice, exercise and L-lactate injection, capillary density and VEGFA quantification

    PMID:28534495

    Open questions at the time
    • Signaling pathway from receptor to VEGFA not delineated
    • Cell-autonomous source of VEGFA not pinned down
  4. 2017 Medium

    Linking HCAR1 activation to BRCA1/NBS1 upregulation and to ABCB1 transporter induction in HeLa cells suggested a PKC-dependent role for the receptor in cancer cell DNA repair and chemoresistance.

    Evidence Agonist (DHBA) treatment, siRNA silencing, immunocytochemistry, comet/γ-H2AX and doxorubicin accumulation assays with PKC inhibitor

    PMID:28258841 PMID:29151072

    Open questions at the time
    • Single cell line and single lab
    • Mechanistic link from PKC to transcriptional targets not resolved
    • In vivo relevance untested
  5. 2019 High

    Defining HCAR1 as a presynaptic, Gαi-coupled suppressor of neuronal network activity that cross-talks with A1, GABAB and α2A receptors established its core neuromodulatory mechanism.

    Evidence Whole-cell patch clamp, calcium imaging and pharmacology in WT vs HCAR1 KO cortical neurons

    PMID:30926749

    Open questions at the time
    • Nature of receptor cross-talk (heteromer vs convergent signaling) unresolved
    • Endogenous lactate dynamics in vivo not measured
  6. 2019 High

    Demonstrating that lactate hyperpolarizes neurons and reduces epileptiform activity via Gβγ-GIRK channel activation identified the effector branch responsible for HCAR1's anti-excitatory action.

    Evidence Patch clamp on rat hippocampal slices with HCA1 agonist and GIRK blocker (tertiapin-Q)

    PMID:31755997

    Open questions at the time
    • Relative contribution of cAMP vs GIRK not quantified
    • Single lab
  7. 2020 High

    Establishing the AMPK-SREBP1-SCD1 axis downstream of HCAR1/MCT1 lactate uptake explained how the receptor confers ferroptosis resistance in hepatocellular carcinoma.

    Evidence In vitro HCC assays with HCAR1/MCT1 inhibition, AMPK/SREBP1/SCD1 readouts and in vivo tumor models

    PMID:33296645

    Open questions at the time
    • Separation of receptor signaling from MCT1 metabolic uptake incomplete
    • Generality across tumor types untested here
  8. 2020 Medium

    Showing HCAR1-dependent V-SVZ neurogenesis and CP/ventricular localization expanded the receptor's role from neuromodulation to regenerative and developmental processes.

    Evidence WT vs HCA1 KO mice with exercise/lactate injection and proliferation/neuroblast markers; mRFP-HCA1 reporter mouse localization

    PMID:32899645 PMID:33244894

    Open questions at the time
    • Niche-specific signaling distinct from neuronal Gαi branch not defined
    • Cell-autonomous vs paracrine action unresolved
  9. 2021 High

    Demonstrating PKA/PKC-dependent axon growth and projection guidance in retinal ganglion cells established HCAR1 as a developmental signaling receptor in the visual system.

    Evidence Retinal explant cultures, PKA/PKC inhibitors, gpr81 KO mice and in vivo projection analysis

    PMID:34208876

    Open questions at the time
    • Connection of cAMP/PKA suppression to growth-cone dynamics not mechanistically closed
    • Single developmental window examined
  10. 2022 Medium

    Genetic dissection in the hypoxic-ischemic and seizure contexts showed HCAR1 is required for regenerative and immune responses while also revealing context-dependent, even opposing, effects on ischemic injury.

    Evidence HCAR1 KO neonatal HI model with transcriptomics and microglial markers; MCAO and microglial phagocytosis assays; human and mouse epileptic slice electrophysiology

    PMID:35240875 PMID:35411485 PMID:35629969 PMID:35942676

    Open questions at the time
    • Contradictory ischemia outcomes (KO smaller lesions) unresolved
    • Cell-type responsible for transcriptome divergence not isolated
  11. 2023 Medium

    Linking HCAR1 to PI3K/Akt-driven NOX4 induction in chondrocytes showed the receptor can also drive ROS production and tissue damage, broadening its signaling repertoire beyond cAMP suppression.

    Evidence Human chondrocyte cultures, PI3K/Akt analysis, NOX4 inhibitor and in vivo intra-articular lactate OA model

    PMID:37688977

    Open questions at the time
    • Reconciliation of pro-damage NOX4 axis with protective roles elsewhere unclear
    • Single lab
  12. 2024 Medium

    Studies in stroke, retinal pigment epithelium, and developing hippocampus refined HCAR1's role in angiogenesis, choroidal development via ISR control, and tonic suppression of seizure susceptibility.

    Evidence HCAR1 KO mice with stroke (dMCAO) lesion/angiogenesis measures; RPE-specific KO with ER stress/eIF2α and ISR rescue; KO EEG seizure analysis with LDHa inhibition

    PMID:38279234 PMID:38655197 PMID:39332673

    Open questions at the time
    • Mechanism connecting HCAR1 to integrated stress response unresolved
    • Failure of synthetic agonist to modulate seizures in vivo attributed to endogenous lactate competition but not proven
  13. 2025 High

    Structural and signaling-profiling studies plus tumor-immune and osteosarcoma work resolved the receptor's ligand recognition mechanism, its β-arrestin-independent transducer bias, and distinct oncogenic effector branches.

    Evidence Cryo-EM HCAR1-Gi1 structures with mutagenesis and cAMP assays; ebBRET transducer profiling with novel agonists/PAM; Hcar1 KO colorectal tumor model with chemokine/immune profiling; co-IP and PP2A inhibitor studies in osteosarcoma

    PMID:39905201 PMID:40233099 PMID:40956299 PMID:41435849

    Open questions at the time
    • β-arrestin2/PP2A recruitment (osteosarcoma) contrasts with reported lack of arrestin recruitment—context dependence unresolved
    • Structural basis of biased signaling not directly addressed
  14. 2026 High

    Refined cryo-EM, astrocytic, epithelial barrier and axonal/seizure studies established the self-activation mechanism, lactate's weak binding mode, and additional tissue-specific outputs of HCAR1 signaling.

    Evidence Cryo-EM apo/L-lactate/CHBA structures with ECL2 mutagenesis; astrocyte siRNA with Ca2+/glutamate and POMC patch clamp; Caco2 apical lactate barrier assays with pertussis toxin; HCAR1 KO axon/myelin and neonatal HI seizure analysis

    PMID:40345852 PMID:41493973 PMID:41616468 PMID:41744475 PMID:41945430

    Open questions at the time
    • How astrocytic Gαi coupling produces Ca2+ rises and hemichannel opening mechanistically unclear
    • Apical-specific localization in epithelia structurally unexplained

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single receptor reconciles its β-arrestin-independent profile with arrestin/PP2A recruitment in tumor cells, and how Gαi-cAMP suppression generates the divergent downstream outputs (Ca2+ rises, NOX4-ROS, ISR control) across cell types, remains unresolved.
  • No unified model linking transducer engagement to cell-type-specific effectors
  • Endogenous lactate concentration thresholds for activation in each tissue undefined
  • Therapeutic agonist efficacy limited by endogenous lactate competition

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-112316 Neuronal System 4 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 3
Partners
ARRB2GNAI1MCT1PP2A

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2025 Cryo-EM structures of human HCAR1 in complex with Gi1 protein were solved at 3.16 Å (with agonist CHBA) and 3.36 Å (apo form), revealing the ligand recognition pocket, receptor activation mechanism, and G protein coupling interface. Mutagenesis and cellular functional assays identified key residues determining ligand selectivity between HCAR1 and HCAR2. The orthosteric pocket of HCAR1 is smaller and more compact than HCAR2, explaining subtype selectivity. Cryo-EM structure determination + site-directed mutagenesis + cellular cAMP functional assays PLoS biology High 40233099
2026 Cryo-EM structures of HCAR1-Gαi1 complex in apo, L-lactate-bound, and CHBA-bound states revealed that HCAR1 has a compact binding pocket stabilized by three unique disulfide bonds. L-lactate shows flexible binding with weak intermolecular interactions (requiring millimolar concentrations), while CHBA binds more stably via its chlorinated benzene ring. Self-activation of HCAR1 is driven by conformational rearrangements in extracellular loop 2, with Phe168(ECL2) acting as a key intrinsic agonist. Cryo-EM structure determination + structural comparison with HCAR2 + mutagenesis Science signaling High 41493973
2025 Using ebBRET assays, HCAR1 was shown to preferentially activate Gαi/o and Gαs pathways without recruiting β-arrestins, revealing a distinct signaling profile. AZ7136 was identified as a potent HCAR1 agonist, AZ2114 as a partial agonist, and GPR81 agonist 1 as an ago-positive allosteric modulator of HCAR1. Enhanced bystander bioluminescence resonance energy transfer (ebBRET) assays for G protein activation and β-arrestin recruitment British journal of pharmacology High 41435849
2019 HCAR1 activation in primary cortical neurons causes downmodulation of neuronal network activity through presynaptic mechanisms (decreased miniature EPSC frequency, increased paired-pulse ratio) and reduced neuronal excitability. HCAR1 signals through Gαi-protein, engaging the adenylyl cyclase-cAMP-PKA axis. HCAR1 functionally interacts with adenosine A1, GABAB, and α2A-adrenergic receptors through both Gαi and Gβγ subunits. HCAR1 KO neurons showed increased basal activity compared to WT. Whole-cell patch clamp, fast calcium imaging, pharmacological inhibitors, comparison of WT vs. HCAR1 KO neurons The Journal of neuroscience High 30926749
2017 HCAR1 is highly enriched in pial fibroblast-like cells lining brain vessels and in pericyte-like cells along intracerebral microvessels. Activation of HCAR1 by lactate (via exercise or subcutaneous L-lactate injection) increases brain VEGFA protein and capillary density in wild-type mice but not in HCAR1 KO mice, demonstrating HCAR1-dependent cerebral angiogenesis. Immunohistochemistry, HCAR1 KO mouse model, exercise and subcutaneous L-lactate injection, capillary density measurement, VEGFA protein quantification Nature communications High 28534495
2022 Activation of HCAR1 with a non-metabolized agonist decreased spontaneous neuronal Ca2+ spiking frequency and excitatory post-synaptic currents (sEPSCs) in human brain slices from epileptic patients. In mouse brain, HCAR1 is expressed in dentate gyrus mossy cells; its activation reduces excitability, sEPSCs, and miniature EPSC frequency in granule cells. Pharmacological HCAR1 activation in human brain slices (patch clamp, Ca2+ imaging), fluorescent reporter mouse line, in situ hybridization, whole-cell patch clamp in mouse and rat slices Journal of cerebral blood flow and metabolism High 35240875
2019 Lactate reduces epileptiform activity in rat subicular neurons through HCA1/GIRK channel activation. HCA1 activation hyperpolarizes subicular neurons and reduces spike frequency via Gβγ subunit and GIRK (G protein-coupled inwardly rectifying potassium) channel activation. Intracellular cAMP is also involved. Patch clamp electrophysiology on rat hippocampal slices, pharmacological HCA1 agonist, GIRK channel blocker (tertiapin-Q), immunohistochemistry Epilepsia High 31755997
2016 GPR81/HCAR1 is expressed in uterine myometrium and its expression increases during gestation, peaking near labor. Lactate acting via GPR81 decreases IL-1β-induced transcription of proinflammatory genes (Il1b, Il6, Ccl2, Pghs2) in myometrial smooth muscle cells and ex vivo uteri. These suppressive effects were absent in GPR81 KO mice or shRNA-GPR81-treated cells. GPR81 silencing augmented proinflammatory gene expression and preterm birth. Primary myometrial smooth muscle cell culture, ex vivo uterus, shRNA knockdown, GPR81 KO mice, endotoxin-induced preterm birth model American journal of obstetrics and gynecology High 27615440
2020 Lactate acts via HCAR1 (HCA1) to induce neurogenesis in the ventricular-subventricular zone (V-SVZ). Exercise or L-lactate injection increased proliferating cells (Ki-67+) and immature neurons (doublecortin+) in the V-SVZ of wild-type but not HCA1 KO mice. In contrast, subgranular zone neurogenesis was induced by exercise in both genotypes but was unaffected by lactate treatment alone. Wild-type vs. HCA1 KO mice, exercise protocol and subcutaneous L-lactate injection, Ki-67 and doublecortin immunolabeling Acta physiologica High 33244894
2022 HCAR1 KO mice showed reduced tissue regeneration, impaired proliferation of neural progenitor cells and glial cells, and impaired microglial activation after neonatal hypoxia-ischemia. Transcriptome analysis revealed approximately 7300 genes responding to HI in WT subventricular zone versus only ~750 in HCAR1 KO, with cell cycle and innate immunity pathways dysregulated in KO mice. HCAR1 KO mouse model, neonatal HI model, transcriptome analysis, immunolabeling for cell proliferation and microglial markers eLife High 35942676
2020 HCAR1-mediated lactate uptake via MCT1 promotes ATP production in hepatocellular carcinoma (HCC) cells, deactivating AMPK, which upregulates SREBP1 and downstream SCD1 to enhance production of anti-ferroptotic monounsaturated fatty acids. Blocking lactate uptake via HCAR1/MCT1 inhibition promotes ferroptosis by activating AMPK to downregulate SCD1 and amplifying ACSL4-dependent ferroptotic susceptibility. In vitro HCC cell assays, HCAR1/MCT1 inhibition, AMPK activity assays, SREBP1/SCD1 expression analysis, in vivo tumor models Cell reports High 33296645
2021 HCAR1/GPR81 is expressed in retinal ganglion cells (RGCs) during visual system development. Activation of GPR81 with L-lactate or 3,5-DHBA alters growth cone morphology (increasing size and filopodia number) and promotes RGC axon growth in retinal explants. These effects were mediated by protein kinases A and C and were absent in gpr81 KO explants. Living gpr81 KO mice showed decreased ipsilateral RGC projections to the dorsal lateral geniculate nucleus. Immunohistochemistry, retinal explant cultures, pharmacological PKA/PKC inhibitors, gpr81 KO mice, in vivo projection analysis Cells High 34208876
2017 HCAR1 activation by DHBA upregulates BRCA1 and NBS1 expression in HeLa cells, with increased nuclear accumulation of BRCA1, nibrin, and DNA-PKcs. This translates into enhanced DNA repair rate after doxorubicin treatment. HCAR1 silencing decreased BRCA1 and NBS1 mRNA/protein and reduced DNA repair efficiency. The DHBA-driven BRCA1 upregulation and enhanced DNA repair were abrogated by PKC inhibitor Gö6983. HCAR1 agonist (DHBA) treatment, HCAR1 siRNA silencing, immunocytochemistry, γ-H2AX and comet assays, PKC inhibitor DNA repair Medium 28258841
2017 HCAR1 activation by L-lactate, D-lactate, or DHBA upregulates ABCB1 (P-glycoprotein) transporter mRNA and protein in HeLa cervical cancer cells, reducing doxorubicin accumulation. HCAR1 silencing decreased ABCB1 expression by 80% (mRNA) and 40% (protein) and increased accumulation of ABCB1 substrates. DHBA-stimulated ABCB1 upregulation was suppressed by PKC pathway inhibition. HCAR1 agonists, siRNA silencing, qPCR, western blot, doxorubicin accumulation assay, PKC inhibitor, cell viability and annexin V assays Journal of physiology and pharmacology Medium 29151072
2023 Lactate activates HCAR1 to upregulate NOX4 expression in chondrocytes via the PI3K/Akt signaling pathway, increasing NADPH oxidase-dependent ROS generation and contributing to osteoarthritis cartilage damage. Lactate also acts metabolically by shunting glucose to the pentose phosphate pathway to increase NADPH levels. Human chondrocyte cultures, HCAR1 receptor activation, PI3K/Akt pathway analysis, NOX4 inhibitor GLX351322, ROS measurement, in vivo intra-articular lactate injection in rat OA model Redox biology Medium 37688977
2012 Naturally occurring missense variants of HCA1 (A110V, S172L, D253H) show reduced basal activity in luciferase reporter assays; S172L shows decreased potency for L-lactate and both S172L and D253H show impaired cell surface expression. Knockdown of HCA1 with siRNA in differentiating OP9 adipocytes increased lipid accumulation, demonstrating HCA1's role in regulating lipid homeostasis in adipocytes. Transient expression in HEK293 cells, luciferase reporter gene assays, siRNA knockdown in OP9 adipocytes, Nile Red staining and TLC for lipid quantification Journal of lipid research Medium 23268337
2024 HCAR1 activation (HCAR1-dependent) by L-lactate administered 24 h and 48 h after experimental stroke reduced lesion volume and enhanced angiogenesis in wild-type mice but not in HCAR1 KO mice. HCAR1 KO mice had smaller lesion volumes than WT controls regardless of L-lactate treatment, indicating a multifactorial role of HCAR1 in stroke outcome. Permanent distal MCA occlusion in WT vs. HCAR1 KO mice, IP L-lactate injection, Nissl-stained lesion volume measurement, immunolabeling for capillary density and neurogenesis International journal of molecular sciences Medium 38279234
2022 HCAR1 activation did not provide neuroprotection in wild-type mice subjected to MCAO; HCAR1 KO mice actually showed smaller ischemic lesions and better behavioral outcomes than wild-type mice, indicating that lactate-mediated protection from ischemia is not achieved through HCAR1 activation (negative finding for HCAR1-mediated neuroprotection in this model). HCAR1 KO and WT mice subjected to transient MCAO, HCAR1 agonist administration at reperfusion, lesion volume measurement, behavioral outcome assessment Metabolites Medium 35629969
2022 HCAR1-mediated L-lactate signaling suppresses microglial phagocytosis in a receptor-dependent but MCT1-independent manner. L-lactate reduces microglial phagocytic capacity through HCAR1. Microglial phagocytosis assay, pharmacological HCAR1 activation, comparison with MCT1-dependent effects Neuromolecular medicine Medium 35411485
2020 HCA1 is localized in fibroblasts of the choroid plexus (CP), tela choroidea, and neuroepithelial ventricular lining of the dorsal third ventricle, as well as in ependymal cells of the tela choroidea and ventricle lining. Co-labeling identified specific cell types using mRFP-HCA1 reporter mice. mRFP-HCA1 reporter mouse line, fluorescence microscopy, co-labeling with cell-type markers International journal of molecular sciences Medium 32899645
2025 HCAR1 activation by lactate in colorectal tumor cells induces expression of chemokines CCL2 and CCL7, leading to recruitment of immunosuppressive CCR2+ PMN-MDSCs to the tumor microenvironment. Ablation of Hcar1 decreased tumor-infiltrating CCR2+ PMN-MDSCs, enhanced CD8+ T cell activation, and reduced tumor burden. Reserpine suppressed lactate-mediated HCAR1 activation and impaired PMN-MDSC recruitment. Hcar1 KO mouse colorectal tumor model, chemokine expression analysis, flow cytometry for immune cell profiling, in vivo tumor burden measurement, pharmacological HCAR1 inhibition with reserpine Nature immunology High 39905201
2025 Lactate-activated HCAR1 promotes osteosarcoma progression by recruiting β-Arrestin2 to facilitate PP2A interaction with phosphorylated STAT1/2, resulting in STAT1/2 dephosphorylation and suppression of anti-oncogenic transcription. PP2A inhibitor Endothall abolished HCAR1-mediated STAT1/2 dephosphorylation and inhibited cancer cell proliferation. Co-immunoprecipitation, western blot for phospho-STAT1/2, PP2A inhibitor treatment, gain/loss-of-function experiments in osteosarcoma cells Advanced science Medium 40956299
2024 HCAR1-deficient mice exhibit lowered seizure thresholds, increased seizure severity and duration. Absence of HCAR1 led to uncontrolled inter-ictal activity in acute hippocampal slices. Lactate dehydrogenase A inhibition recapitulated the HCAR1 KO phenotype, indicating HCAR1 activation is coupled to glycolytic output. However, synthetic HCAR1 agonist administration in vivo did not modulate seizures, likely due to endogenous lactate competition. HCAR1 KO mice, in vivo EEG seizure analysis, acute hippocampal slice electrophysiology, LDHa inhibitor treatment, time-frequency analysis iScience Medium 38655197
2026 HCAR1 HCAR1 KO mice showed reduced axonal area in cortex and corpus callosum predominantly in unmyelinated axons, without effect on myelin area. In an organotypic brain slice model of neonatal hypoglycemia, lactate protected both axonal and myelin development partially via HCAR1. Live imaging indicated that cellular lactate uptake is influenced by HCAR1. HCAR1 KO mice, particle and colocalization analysis of axon/myelin markers, organotypic brain slice hypoglycemia model, live pH-sensitive dye imaging eNeuro Medium 40345852
2024 HCAR1 is exclusively expressed in RPE cells within the subretina. HCAR1-deficient mice exhibit substantially thinner choroidal vasculature during development, with impaired lactate-induced angiogenic effects. HCAR1 deficiency elevates endoplasmic reticulum stress and eIF2α phosphorylation, reduces global protein translation and choroidal cell proliferation. Inhibition of the integrated stress response (ISR) rescued protein translation and choroidal thinning. HCAR1 KO mouse model, immunohistochemistry, choroidal vascular measurement, ER stress markers, eIF2α phosphorylation assay, ISR inhibitor rescue experiment The American journal of pathology Medium 39332673
2025 In hyperglycemic podocytes, GPR81/HCAR1 expression decreases and the cAMP/PKA signaling pathway is downregulated, leading to reduced ATGL and Perilipin-1 expression, lipid droplet accumulation, and lipolysis inhibition. These changes associate with increased albumin permeability and actin cytoskeleton rearrangement. ATGL inhibition phenocopied GPR81 downregulation effects, identifying GPR81 as a lipid-sensing regulator of podocyte lipolysis and cytoskeletal integrity. Primary podocyte cultures under hyperglycemia, cAMP/PKA pathway assay, ATGL and Perilipin-1 expression, lipid droplet quantification, glycerol/fatty acid measurement, albumin permeability assay Journal of cellular physiology Medium 39962919
2026 Astrocytic HCAR1 is highly expressed in hypothalamic astrocytes. L-lactate activation of astrocytic HCAR1 elicits cytosolic Ca2+ increases and stimulates glutamate release (both abolished by HCAR1 siRNA silencing). L-lactate and 3Cl-HBA increased connexin hemichannel activity, and hemichannel inhibition reduced glutamate release. Focal intracellular glucose delivery to a single tanycyte triggered rapid Ca2+ elevations in neighboring astrocytes. Astrocytic HCAR1 activation enhanced NMDA receptor-dependent slow inward currents and excitability in POMC neurons; this was abolished by astrocytic HCAR1 silencing. siRNA silencing of astrocytic HCAR1, Ca2+ imaging, glutamate release assay, connexin hemichannel inhibition, patch clamp on POMC neurons in acute hypothalamic slices, single tanycyte glucose microinjection Proceedings of the National Academy of Sciences of the United States of America High 41945430
2026 HCAR1 activation by apical (but not basal) L- and D-lactate enhances tight junctions and reduces permeability in differentiated Caco2 colonic epithelial cells via Gαi signaling. Apical lactate also rescued LPS-induced barrier dysfunction. The effect is consistent with HCAR1's apical membrane localization. Caco2 cell differentiation, apical vs. basal lactate treatment, Gαi inhibitor (pertussis toxin), tight junction and permeability assays, LPS barrier disruption model Biomedicine & pharmacotherapy Medium 41616468
2026 HCAR1 expression on neonatal hippocampal neurons was confirmed by qRT-PCR. Lactate decreased sEPSC amplitude and frequency in wild-type but not HCAR1 KO hippocampal neurons. HCAR1 KO mice subjected to neonatal hypoxia-ischemia had significantly higher seizure burden and behavioral seizure scores than wild-type, and HCAR1 expression increased 24h post-HI then dropped below baseline by 48h. qRT-PCR, patch clamp electrophysiology in HCAR1 KO vs. WT hippocampal neurons, neonatal HI model with EEG monitoring Epilepsia Medium 41744475

Source papers

Stage 0 corpus · 51 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 Exercise induces cerebral VEGF and angiogenesis via the lactate receptor HCAR1. Nature communications 408 28534495
2020 HCAR1/MCT1 Regulates Tumor Ferroptosis through the Lactate-Mediated AMPK-SCD1 Activity and Its Therapeutic Implications. Cell reports 352 33296645
2019 The Lactate Receptor HCAR1 Modulates Neuronal Network Activity through the Activation of Gα and Gβγ Subunits. The Journal of neuroscience : the official journal of the Society for Neuroscience 144 30926749
2017 The lactate receptor (HCAR1/GPR81) contributes to doxorubicin chemoresistance via ABCB1 transporter up-regulation in human cervical cancer HeLa cells. Journal of physiology and pharmacology : an official journal of the Polish Physiological Society 86 29151072
2023 Lactate-upregulated NADPH-dependent NOX4 expression via HCAR1/PI3K pathway contributes to ROS-induced osteoarthritis chondrocyte damage. Redox biology 83 37688977
2016 Lactate produced during labor modulates uterine inflammation via GPR81 (HCA1). American journal of obstetrics and gynecology 73 27615440
2022 Lactate receptor HCAR1 regulates neurogenesis and microglia activation after neonatal hypoxia-ischemia. eLife 62 35942676
2022 Activation of lactate receptor HCAR1 down-modulates neuronal activity in rodent and human brain tissue. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 52 35240875
2025 The lactate receptor HCAR1 drives the recruitment of immunosuppressive PMN-MDSCs in colorectal cancer. Nature immunology 50 39905201
2020 L-lactate induces neurogenesis in the mouse ventricular-subventricular zone via the lactate receptor HCA1. Acta physiologica (Oxford, England) 50 33244894
2022 Lactate Induces the Expressions of MCT1 and HCAR1 to Promote Tumor Growth and Progression in Glioblastoma. Frontiers in oncology 49 35574309
2021 Participation of L-Lactate and Its Receptor HCAR1/GPR81 in Neurovisual Development. Cells 39 34208876
2019 Differential effects of L- and D-lactate on memory encoding and consolidation: Potential role of HCAR1 signaling. Neurobiology of learning and memory 38 31881352
2017 Stimulation of lactate receptor (HCAR1) affects cellular DNA repair capacity. DNA repair 35 28258841
2023 Curcumin derivative NL01 induces ferroptosis in ovarian cancer cells via HCAR1/MCT1 signaling. Cellular signalling 31 37406786
2023 History and Function of the Lactate Receptor GPR81/HCAR1 in the Brain: A Putative Therapeutic Target for the Treatment of Cerebral Ischemia. Neuroscience 30 37391123
2022 Lactate receptor HCAR1 regulates cell growth, metastasis and maintenance of cancer‑specific energy metabolism in breast cancer cells. Molecular medicine reports 26 35775372
2022 Lactate Neuroprotection against Transient Ischemic Brain Injury in Mice Appears Independent of HCAR1 Activation. Metabolites 21 35629969
2011 Cytotoxic angucyclines from Amycolatopsis sp. HCa1, a rare actinobacteria derived from Oxya chinensis. Planta medica 19 21830188
2022 Exercise Regulates the Lactate Receptor HCAR1 and ERK1/2-PI3K/Akt Pathways to Promote Cerebral Angiogenesis. Iranian journal of public health 18 36415798
2020 The Lactate Receptor HCA1 Is Present in the Choroid Plexus, the Tela Choroidea, and the Neuroepithelial Lining of the Dorsal Part of the Third Ventricle. International journal of molecular sciences 18 32899645
2019 Lactate reduces epileptiform activity through HCA1 and GIRK channel activation in rat subicular neurons in an in vitro model. Epilepsia 18 31755997
2023 Versatile lactate signaling via HCAR1: a multifaceted GPCR involved in many biological processes. American journal of physiology. Cell physiology 16 37899751
2012 Angucyclines from an insect-derived actinobacterium Amycolatopsis sp. HCa1 and their cytotoxic activity. Bioorganic & medicinal chemistry letters 16 23131338
2024 L-Lactate Treatment at 24 h and 48 h after Acute Experimental Stroke Is Neuroprotective via Activation of the L-Lactate Receptor HCA1. International journal of molecular sciences 14 38279234
2022 HCAR1-Mediated L-Lactate Signaling Suppresses Microglial Phagocytosis. Neuromolecular medicine 12 35411485
2012 Actinotetraoses A-H: tetrasaccharide derivatives from a grasshopper-associated Amycolatopsis sp. HCa1. Planta medica 12 22618372
2022 Evaluation of Hydroxycarboxylic Acid Receptor 1 (HCAR1) as a Building Block for Genetically Encoded Extracellular Lactate Biosensors. Biosensors 7 35323413
2014 Synthesis and evaluation of (E)-2-(acrylamido)cyclohex-1-enecarboxylic acid derivatives as HCA1, HCA2, and HCA3 receptor agonists. Bioorganic & medicinal chemistry 7 24864041
2024 The lactate receptor HCAR1: A key modulator of epileptic seizure activity. iScience 6 38655197
2022 Elevated Circulating Lactate Levels and Widespread Expression of Its Cognate Receptor, Hydroxycarboxylic Acid Receptor 1 (HCAR1), in Ovarian Cancer. Journal of clinical medicine 6 36615018
2012 Naturally occurring HCA1 missense mutations result in loss of function: potential impact on lipid deposition. Journal of lipid research 6 23268337
2024 Immunohistochemical localization of HCA1 receptor in placenta in presence of fetal growth restriction. Placenta 5 38909565
2023 Lack of HCAR1, the lactate GPCR, signaling promotes autistic-like behavior. Cell communication and signaling : CCS 5 37940970
2015 Actinotetraose L, a new tetrasaccharide derivative isolated from the mycelia of Amycolatopsis sp. HCa1. Journal of Asian natural products research 5 26218137
2025 Role of Metabolic Sensor GPR81/HCAR1 in Diabetic Podocytes: Downregulated Lipolysis Results in the Deterioration of Glomerular Filtration Barrier. Journal of cellular physiology 4 39962919
2025 Structures of G-protein coupled receptor HCAR1 in complex with Gi1 protein reveal the mechanistic basis for ligand recognition and agonist selectivity. PLoS biology 4 40233099
2022 Adipose‑derived mesenchymal stem cell‑derived HCAR1 regulates immune response in the attenuation of sepsis. Molecular medicine reports 4 35856408
2021 Discovery of an unprecedented benz[α]anthraquinone-type heterodimer from a rare actinomycete Amycolatopsis sp. HCa1. Fitoterapia 4 34592372
2025 Lactate Activates the HCAR1/β-Arrestin2/PP2A Signaling Axis to Mediate STAT1/2 Dephosphorylation and Drive Osteosarcoma Progression. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 3 40956299
2025 Lactate Receptor HCAR1 Affects Axonal Development and Contributes to Lactate's Protection of Axons and Myelin in Experimental Neonatal Hypoglycemia. eNeuro 2 40345852
2025 HCAR1 Modulates Ferroptosis in Gastric Cancer via Lactate-Mediated AMPK-SCD1 Signaling and Lipid Metabolism. Oncology research 2 41050072
2025 Profiling of HCAR1 signalling reveals Gαi/o and Gαs activation without β-arrestin recruitment and the discovery of an allosteric agonist. British journal of pharmacology 1 41435849
2024 Endoplasmic Reticulum Stress Delays Choroid Development in the HCAR1 Knockout Mouse. The American journal of pathology 1 39332673
2026 Structural insights into the activation mechanism of the human metabolite receptor HCAR1. Science signaling 0 41493973
2026 D- and L-Lactate enhance intestinal barrier function via activation of an apical HCAR1/Gαi pathway in a human colonic epithelial cell model. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 0 41616468
2026 HCAR1 antagonist screening based on boundary-selected negative sampling strategy and multi-level graph neural network. Computer methods and programs in biomedicine 0 41633067
2026 A Machine Learning-Guided Approach for Identifying Potential HCAR1 Antagonists in Lactate-Driven Cancers. ACS omega 0 41726659
2026 Lactate receptor HCAR1 in neonatal hypoxic-ischemic seizures. Epilepsia 0 41744475
2026 Arenobufagin induces ferroptosis in gastric cancer stem cells via the HCAR1-GPX4/SLC7A11 antioxidant axis. European journal of pharmacology 0 41856196
2026 Tanycyte-derived lactate activates astrocytic HCAR1 to modulate glutamatergic signaling and POMC neuron excitability. Proceedings of the National Academy of Sciences of the United States of America 0 41945430

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