CASR

Summary: Rat-derived ossification inference requires its tissue-specific donor evidence.

Reason: This electronic transfer is not established merely by human systemic calcium imbalance. The exact rat donor experiment and its bone-cell or developmental mechanism remain to be resolved; the source assertion is preserved without claiming that CASR cannot affect ossification.

Summary: The historical ossification assertion is not resolved by the accessible clinical abstract.

Reason: PMID:7874174 supports altered calcium sensing and a hypocalcemic phenotype, but the complete primary text was not retrieved. A direct contribution to ossification cannot be distinguished from a systemic mineral phenotype using this access alone.

Summary: The ischemia-response transfer lacks inspected donor endpoint evidence.

Reason: The source transfers rat Casr evidence. Neither receptor identity nor generic calcium signaling establishes the particular ischemic response, and the relevant donor experiment has not been independently read.

Summary: Phylogenetically inherited GPCR activity agrees with direct human receptor evidence.

Reason: The PAINT assertion represents an ancestral functional inference, not a count of pairwise donors. Direct human CASR signaling and receptor-G-protein structures support retention. The target appearing among the descendant evidence is legitimate and is not circular.

Summary: Human CASR functions as a ligand-regulated G protein-coupled receptor.

Reason: The complete abstract reports coexpression of inactive human CaSR mutant pairs in HEK293 cells, partial signaling rescue for selected combinations and biochemical heterodimers. This supports receptor function and functional communication between subunits. The cache is abstract-only; uninspected controls are not claimed. The receptor transduces an extracellular calcium signal through heterotrimeric G proteins; this is its central molecular function.

Summary: Human CASR functions as a ligand-regulated G protein-coupled receptor.

Reason: The complete abstract describes CaSR-dependent intracellular calcium oscillations, T888 phosphorylation, PKC feedback and phosphatase-sensitive behavior in receptor-expressing HEK293 cells, with a separate bovine parathyroid component. This supports receptor-dependent calcium regulation without identifying CASR as a calcium channel. The cache is abstract-only. The receptor transduces an extracellular calcium signal through heterotrimeric G proteins; this is its central molecular function.

Summary: Human CASR functions as a ligand-regulated G protein-coupled receptor.

Reason: Selected complete structural, ligand-binding, mutational and cellular-assay passages were read. Human extracellular-domain constructs were expressed in insect cells, whereas full-length human receptors were tested in HEK293 cells with surface-expression controls, IP1 and calcium readouts. Scintillation proximity directly demonstrated tryptophan binding; anomalous diffraction supported calcium-binding sites. The paper interprets amino acids as agonists, but later controlled-membrane work distinguishes positive allosteric modulation. Amino-acid binding remains supported irrespective of this activation-model dispute. The receptor transduces an extracellular calcium signal through heterotrimeric G proteins; this is its central molecular function.

Summary: Human CASR functions as a ligand-regulated G protein-coupled receptor.

Reason: Selected complete Results and Discussion passages describe a SNAP-tag TR-FRET receptor sensor, cellular IP1/calcium assays, cell-surface controls, cross-linking and dialyzed membrane preparations. Under the controlled membrane conditions calcium alone drove the full conformational transition, whereas amino acids potentiated calcium responses. This differs from a universal amino-acid-alone agonist interpretation. Detailed experimental protocols delegated to the separate SI Appendix were not independently read. The receptor transduces an extracellular calcium signal through heterotrimeric G proteins; this is its central molecular function.

Summary: Human CASR functions as a ligand-regulated G protein-coupled receptor.

Reason: Selected complete cryo-EM interpretation, construct and cellular-assay passages were read. Full-length human CaSR with substituted signal sequence/tags was expressed in insect cells; HEK293T mutant assays measured IP1 with surface-expression controls. Tryptophan closes the Venus flytrap domain but does not alone complete transmembrane activation; calcium and amino acids cooperate in the authors' model. Ambient ligands and conformational intermediates limit absolute ligand-sufficiency conclusions. The receptor transduces an extracellular calcium signal through heterotrimeric G proteins; this is its central molecular function.

Summary: Human CASR functions as a ligand-regulated G protein-coupled receptor.

Reason: Selected complete structural, engineered-dimer, BRET, IP1 and expression-method passages were read. Human CaSR residues 20-894 were used for structural and cellular assays, with signaling competence assessed; forced dimers used GABAB-derived targeting elements. The results support GPCR signaling, asymmetric activation and allosteric modulation, but engineered targeting constructs and the C-terminal truncation must not be presented as unmodified endogenous receptor behavior. The receptor transduces an extracellular calcium signal through heterotrimeric G proteins; this is its central molecular function.

Summary: Human CASR functions as a ligand-regulated G protein-coupled receptor.

Reason: Selected complete structural, ligand, mutational, expression-control and Discussion passages were read. A human 1-870 construct was purified for structures and full-length mutant receptors were tested in cells. Inhibitory nanobody stabilization and calcium/TNCA/cinacalcet conditions define the structural states. The authors acknowledge that cryo-EM density alone does not uniquely identify calcium and that amino-acid activation terminology remains contested. Cellular calcium responses and expression controls support receptor activity. The receptor transduces an extracellular calcium signal through heterotrimeric G proteins; this is its central molecular function.

Summary: Human CASR functions as a ligand-regulated G protein-coupled receptor.

Reason: The complete abstract and selected complete Results/Methods paragraphs were read. Two complementary cellular BRET approaches primarily support Gi/o and Gq/11 activation, with receptor surface-expression controls. Human receptor constructs include a 20-894 truncation; structural preparations additionally use GABAB-derived tails, tethering and engineered G proteins. These experiments support receptor coupling in the tested systems, not a universal native-tissue G-protein preference or a direct cAMP measurement. The receptor transduces an extracellular calcium signal through heterotrimeric G proteins; this is its central molecular function.

Summary: Human CASR functions as a ligand-regulated G protein-coupled receptor.

Reason: The complete abstract and selected complete construct/functional Methods paragraphs were read. Structures use truncated human receptor and dominant-negative or mini/chimeric G proteins, whereas cellular assays use full-length receptor. Gi/Gs-tail chimeras redirect coupling to an IP1 readout in Gq/11-deficient cells; this is not native Gi/Gs second-messenger measurement. Separate TRUPATH assays address Gi1, Gi3 and Gq. The authors report no detectable CaSR-induced Gs activity in HEK293T or MCF7, although that method paragraph names a Gq donor, an unresolved internal description ambiguity. Surface-expression controls and calcium-dependent FRET-background subtraction are explicit. No universal physiological Gs claim is justified. The receptor transduces an extracellular calcium signal through heterotrimeric G proteins; this is its central molecular function.

Summary: Human CASR functions as a ligand-regulated G protein-coupled receptor.

Reason: The complete abstract reports human CaSR in HEK293 cells, PKC modulators, phosphorylation-site mutants and in-vitro phosphorylation identifying T888 as a major site. It supports feedback regulation of receptor-dependent cytosolic calcium responses; CASR is the kinase substrate, not the kinase. The cache is abstract-only. The receptor transduces an extracellular calcium signal through heterotrimeric G proteins; this is its central molecular function.

Summary: Combined electronic evidence identifies the correct class C GPCR activity.

Reason: The conserved receptor domains and mammalian orthology agree with direct human ligand-dependent signaling. The electronic source is retained rather than treated as an independent experiment.

Summary: Human parathyroid receptor cloning established functional calcium-responsive signaling.

Reason: The complete abstract reports cloning of a 1078-residue human parathyroid calcium-sensing receptor, a rare insertion-containing transcript and functional cation responses in Xenopus oocytes. This supports receptor function and calcium sensing. A complete primary body was not retrieved, and organismal chemosensory behavior cannot be adjudicated from the abstract alone. The fundamental receptor activity is clear, so the historical curator assertion is retained despite incomplete body access.

Summary: The rat-derived integrin-binding assertion needs the actual interaction context.

Reason: An integrin-associated trafficking or signaling complex is not automatically direct CASR-integrin binding. The particular rat donor assay and partner have not yet been independently resolved; no generic receptor-binding assumption is substituted.

Summary: Calcium binding is an inherited and directly demonstrated feature of CASR.

Reason: The PAINT node is consistent with direct human extracellular-domain calcium-binding structures. The self donor is experimental grounding, not circularity. Binding is integrated into the receptor core rather than made a separate catalytic activity.

Summary: The extracellular receptor domain directly binds calcium ions.

Reason: Selected complete structural, ligand-binding, mutational and cellular-assay passages were read. Human extracellular-domain constructs were expressed in insect cells, whereas full-length human receptors were tested in HEK293 cells with surface-expression controls, IP1 and calcium readouts. Scintillation proximity directly demonstrated tryptophan binding; anomalous diffraction supported calcium-binding sites. The paper interprets amino acids as agonists, but later controlled-membrane work distinguishes positive allosteric modulation. Amino-acid binding remains supported irrespective of this activation-model dispute. Calcium recognition is supported even though assignment of individual activation-site roles was refined in later studies.

Summary: Detection of extracellular calcium is the conserved sensory role of CASR.

Reason: The ancestral CaSR-clade assertion agrees with human ligand-response and binding experiments; there is no target-specific evidence of loss of this sensory function.

Summary: Human CASR detects extracellular calcium through ligand-dependent receptor activation.

Reason: Selected complete structural, ligand-binding, mutational and cellular-assay passages were read. Human extracellular-domain constructs were expressed in insect cells, whereas full-length human receptors were tested in HEK293 cells with surface-expression controls, IP1 and calcium readouts. Scintillation proximity directly demonstrated tryptophan binding; anomalous diffraction supported calcium-binding sites. The paper interprets amino acids as agonists, but later controlled-membrane work distinguishes positive allosteric modulation. Amino-acid binding remains supported irrespective of this activation-model dispute. Detection concerns extracellular ligand recognition, not transport of calcium through CASR.

Summary: The rat-to-human calcium-detection inference agrees with direct human measurements.

Reason: Human receptor calcium-binding and concentration-response experiments independently establish this activity, so uncertainty about the detailed donor record does not undermine the correct sensory role.

Summary: The cloned human receptor senses extracellular calcium.

Reason: The complete abstract reports cloning of a 1078-residue human parathyroid calcium-sensing receptor, a rare insertion-containing transcript and functional cation responses in Xenopus oocytes. This supports receptor function and calcium sensing. A complete primary body was not retrieved, and organismal chemosensory behavior cannot be adjudicated from the abstract alone. The clear calcium-sensing phenotype supports curator deference for this established role.

Summary: CASR associates with the trafficking cargo receptor TMED2/p24A.

Reason: Human-kidney two-hybrid screening and reciprocal coimmunoprecipitation of human constructs in HEK293 cells support the source-specific association. The immature receptor associates before Golgi maturation, and TMED2 perturbations alter CASR abundance and surface delivery. CASR is the cargo in this relationship; these data do not make it a cargo receptor, transporter or chaperone. Under the project binding policy the supported interaction is retained non-core without inventing a finer activity.

Summary: CASR is present at the plasma membrane where extracellular calcium can activate it.

Reason: The complete abstract reports human R227Q and R227L receptors expressed in HEK293 cells, comparable glycosylation and cell-surface abundance, and different extracellular-calcium concentration responses. It supports plasma-membrane localization of the tested receptors. The cache is abstract-only. The location describes the receptor population detected at the cell surface; it does not deny intracellular biosynthetic or retained pools.

Summary: CASR is present at the plasma membrane where extracellular calcium can activate it.

Reason: The complete abstract describes total internal reflection fluorescence measurements of agonist-driven CaSR insertion into the plasma membrane, ongoing biosynthetic delivery and constitutive endocytosis. These results support cell-surface localization and dynamic receptor delivery. The cache is abstract-only; detailed imaging controls were not inspected. The location describes the receptor population detected at the cell surface; it does not deny intracellular biosynthetic or retained pools.

Summary: Plasma-membrane localization is conserved and directly corroborated in human CASR.

Reason: The PAINT assertion agrees with surface-expression and trafficking experiments. Human target evidence among the donors supports the ancestral judgment and is not circular.

Summary: CASR is present at the plasma membrane where extracellular calcium can activate it.

Reason: The complete abstract reports surface localization of wild-type receptor, ER retention of R66H, R66C and N583X mutants, and FRET evidence for wild-type and R66H/R66C dimers. Dimerization is necessary but not sufficient for efficient export in this experiment. The cache is abstract-only, so the full imaging and FRET controls were not independently inspected. The location describes the receptor population detected at the cell surface; it does not deny intracellular biosynthetic or retained pools.

Summary: CASR is present at the plasma membrane where extracellular calcium can activate it.

Reason: The complete abstract reports a de novo heterozygous R551K variant in cis with A986S in one child with neonatal severe hyperparathyroidism, later mild hypercalcemia, and reduced calcium sensitivity in HEK293 cells. It supports receptor signaling and localization; this family-specific presentation does not redefine the usual recessive severe-disease association. The cache is abstract-only. The location describes the receptor population detected at the cell surface; it does not deny intracellular biosynthetic or retained pools.

Summary: CASR is present at the plasma membrane where extracellular calcium can activate it.

Reason: The complete abstract reports Q459R in a consanguineous family, mild hypercalcemia in homozygotes, largely normal heterozygotes, and reduced signaling despite cell-surface expression. This is a particular allele/family with apparent recessive mild disease, not a universal inheritance rule. The cache is abstract-only. The location describes the receptor population detected at the cell surface; it does not deny intracellular biosynthetic or retained pools.

Summary: CASR is present at the plasma membrane where extracellular calcium can activate it.

Reason: Selected complete Methods, Results and Discussion passages from the normal HTML cache show FLAG-tagged human CaSR expressed in HEK293 cells, background-corrected surface/total ELISA, ERK responses, arginine-motif mutants and phosphorylation-site substitutions. They support regulated surface abundance. The historical epilepsy implication is not accepted as current gene-disease validity; the frozen ClinGen record classifies that association as refuted. Cellular trafficking results and disease causality are separate claims. Direct 14-3-3 binding was explicitly left unresolved by the authors. The location describes the receptor population detected at the cell surface; it does not deny intracellular biosynthetic or retained pools.

Summary: CASR is present at the plasma membrane where extracellular calcium can activate it.

Reason: The complete abstract reports Q681R and P221L in hypocalcemic families and functional testing of Q681R in HEK293 cells, with increased calcium sensitivity despite similar expression and surface targeting. It supports receptor localization and signaling. The cache is abstract-only. The location describes the receptor population detected at the cell surface; it does not deny intracellular biosynthetic or retained pools.

Summary: CASR is present at the plasma membrane where extracellular calcium can activate it.

Reason: The complete abstract reports Myc-tagged human CaSR expression in HEK293 cells, absent detectable E707V expression and reduced signaling sensitivity for G774S, with additional family screening. This supports receptor signaling and the tested localization observations, not a conclusion that all hypercalcemic families have CASR variants. The cache is abstract-only. The location describes the receptor population detected at the cell surface; it does not deny intracellular biosynthetic or retained pools.

Summary: CASR is present at the plasma membrane where extracellular calcium can activate it.

Reason: The complete abstract reports human P136L CaSR in HEK293 cells, surface localization, increased intracellular-calcium and MAPK responses, and segregation with hypocalcemia in a family. This supports the tested receptor localization and signaling. The cache is abstract-only. The location describes the receptor population detected at the cell surface; it does not deny intracellular biosynthetic or retained pools.

Summary: CASR is present at the plasma membrane where extracellular calcium can activate it.

Reason: The complete abstract reports human G571W CaSR in COS7 cells, surface expression comparable to wild type and reduced Fura-2 calcium responses. This supports receptor signaling and localization, with no claim to have inspected the complete imaging controls. The cache is abstract-only. The location describes the receptor population detected at the cell surface; it does not deny intracellular biosynthetic or retained pools.

Summary: CASR is present at the plasma membrane where extracellular calcium can activate it.

Reason: The complete abstract reports eight human CaSR variants expressed in HEK293 cells, calcium/gadolinium responses, glycosylation and surface-expression differences. It supports receptor signaling and localization. Trafficking versus coupling defects are interpreted within each mutant context. The cache is abstract-only. The location describes the receptor population detected at the cell surface; it does not deny intracellular biosynthetic or retained pools.

Summary: Electronic plasma-membrane localization agrees with direct human receptor assays.

Reason: The multipass receptor topology and orthology are supported by specific cell-surface experiments; retained intracellular mutant pools do not negate wild-type surface localization.

Summary: CASR is present at the plasma membrane where extracellular calcium can activate it.

Reason: The complete abstract reports cloning of a 1078-residue human parathyroid calcium-sensing receptor, a rare insertion-containing transcript and functional cation responses in Xenopus oocytes. This supports receptor function and calcium sensing. A complete primary body was not retrieved, and organismal chemosensory behavior cannot be adjudicated from the abstract alone. The location describes the receptor population detected at the cell surface; it does not deny intracellular biosynthetic or retained pools.

Summary: The Reactome membrane-receptor event is consistent with CASR surface localization.

Reason: The source is a human receptor-signaling event, not a separate localization experiment. Direct human surface-versus-total assays independently establish plasma-membrane CASR. The generic Gq/Gi event summaries are not claimed to supply target-specific microscopy or binding controls.

Summary: The Reactome membrane-receptor event is consistent with CASR surface localization.

Reason: The source is a human receptor-signaling event, not a separate localization experiment. Direct human surface-versus-total assays independently establish plasma-membrane CASR. The generic Gq/Gi event summaries are not claimed to supply target-specific microscopy or binding controls.

Summary: The Reactome membrane-receptor event is consistent with CASR surface localization.

Reason: The source is a human receptor-signaling event, not a separate localization experiment. Direct human surface-versus-total assays independently establish plasma-membrane CASR. The generic Gq/Gi event summaries are not claimed to supply target-specific microscopy or binding controls.

Summary: The Reactome membrane-receptor event is consistent with CASR surface localization.

Reason: The source is a human receptor-signaling event, not a separate localization experiment. Direct human surface-versus-total assays independently establish plasma-membrane CASR. The generic Gq/Gi event summaries are not claimed to supply target-specific microscopy or binding controls.

Summary: The Reactome membrane-receptor event is consistent with CASR surface localization.

Reason: The source is a human receptor-signaling event, not a separate localization experiment. Direct human surface-versus-total assays independently establish plasma-membrane CASR. The generic Gq/Gi event summaries are not claimed to supply target-specific microscopy or binding controls.

Summary: The Reactome membrane-receptor event is consistent with CASR surface localization.

Reason: The source is a human receptor-signaling event, not a separate localization experiment. Direct human surface-versus-total assays independently establish plasma-membrane CASR. The generic Gq/Gi event summaries are not claimed to supply target-specific microscopy or binding controls.

Summary: The Reactome membrane-receptor event is consistent with CASR surface localization.

Reason: The source is a human receptor-signaling event, not a separate localization experiment. Direct human surface-versus-total assays independently establish plasma-membrane CASR. The generic Gq/Gi event summaries are not claimed to supply target-specific microscopy or binding controls.

Summary: The Reactome membrane-receptor event is consistent with CASR surface localization.

Reason: The source is a human receptor-signaling event, not a separate localization experiment. Direct human surface-versus-total assays independently establish plasma-membrane CASR. The generic Gq/Gi event summaries are not claimed to supply target-specific microscopy or binding controls.

Summary: CASR signaling regulates intracellular calcium dynamics.

Reason: The PAINT assertion is consistent with human receptor-dependent calcium mobilization and feedback. GO:0006874 includes regulation of cytosolic calcium concentration among its descendants; the receptor participates through signaling, not by directly transporting or buffering intracellular calcium. Systemic extracellular calcium homeostasis is a distinct physiological level.

Summary: Receptor activation contributes to regulation of intracellular calcium responses.

Reason: The complete abstract describes CaSR-dependent intracellular calcium oscillations, T888 phosphorylation, PKC feedback and phosphatase-sensitive behavior in receptor-expressing HEK293 cells, with a separate bovine parathyroid component. This supports receptor-dependent calcium regulation without identifying CASR as a calcium channel. The cache is abstract-only. Retain the curator's calcium-regulatory assertion in the context of receptor-dependent calcium signaling and feedback; this is not evidence that CASR itself is a calcium channel, pump or intracellular buffer.

Summary: Receptor activation contributes to regulation of intracellular calcium responses.

Reason: Selected complete structural, ligand-binding, mutational and cellular-assay passages were read. Human extracellular-domain constructs were expressed in insect cells, whereas full-length human receptors were tested in HEK293 cells with surface-expression controls, IP1 and calcium readouts. Scintillation proximity directly demonstrated tryptophan binding; anomalous diffraction supported calcium-binding sites. The paper interprets amino acids as agonists, but later controlled-membrane work distinguishes positive allosteric modulation. Amino-acid binding remains supported irrespective of this activation-model dispute. Retain the curator's calcium-regulatory assertion in the context of receptor-dependent calcium signaling and feedback; this is not evidence that CASR itself is a calcium channel, pump or intracellular buffer.

Summary: Receptor activation contributes to regulation of intracellular calcium responses.

Reason: Selected complete Results and Discussion passages describe a SNAP-tag TR-FRET receptor sensor, cellular IP1/calcium assays, cell-surface controls, cross-linking and dialyzed membrane preparations. Under the controlled membrane conditions calcium alone drove the full conformational transition, whereas amino acids potentiated calcium responses. This differs from a universal amino-acid-alone agonist interpretation. Detailed experimental protocols delegated to the separate SI Appendix were not independently read. Retain the curator's calcium-regulatory assertion in the context of receptor-dependent calcium signaling and feedback; this is not evidence that CASR itself is a calcium channel, pump or intracellular buffer.

Summary: Receptor activation contributes to regulation of intracellular calcium responses.

Reason: Selected complete cryo-EM interpretation, construct and cellular-assay passages were read. Full-length human CaSR with substituted signal sequence/tags was expressed in insect cells; HEK293T mutant assays measured IP1 with surface-expression controls. Tryptophan closes the Venus flytrap domain but does not alone complete transmembrane activation; calcium and amino acids cooperate in the authors' model. Ambient ligands and conformational intermediates limit absolute ligand-sufficiency conclusions. Retain the curator's calcium-regulatory assertion in the context of receptor-dependent calcium signaling and feedback; this is not evidence that CASR itself is a calcium channel, pump or intracellular buffer.

Summary: Receptor activation contributes to regulation of intracellular calcium responses.

Reason: Selected complete structural, engineered-dimer, BRET, IP1 and expression-method passages were read. Human CaSR residues 20-894 were used for structural and cellular assays, with signaling competence assessed; forced dimers used GABAB-derived targeting elements. The results support GPCR signaling, asymmetric activation and allosteric modulation, but engineered targeting constructs and the C-terminal truncation must not be presented as unmodified endogenous receptor behavior. Retain the curator's calcium-regulatory assertion in the context of receptor-dependent calcium signaling and feedback; this is not evidence that CASR itself is a calcium channel, pump or intracellular buffer.

Summary: Receptor activation contributes to regulation of intracellular calcium responses.

Reason: Selected complete structural, ligand, mutational, expression-control and Discussion passages were read. A human 1-870 construct was purified for structures and full-length mutant receptors were tested in cells. Inhibitory nanobody stabilization and calcium/TNCA/cinacalcet conditions define the structural states. The authors acknowledge that cryo-EM density alone does not uniquely identify calcium and that amino-acid activation terminology remains contested. Cellular calcium responses and expression controls support receptor activity. Retain the curator's calcium-regulatory assertion in the context of receptor-dependent calcium signaling and feedback; this is not evidence that CASR itself is a calcium channel, pump or intracellular buffer.

Summary: Receptor activation contributes to regulation of intracellular calcium responses.

Reason: The complete abstract and selected complete construct/functional Methods paragraphs were read. Structures use truncated human receptor and dominant-negative or mini/chimeric G proteins, whereas cellular assays use full-length receptor. Gi/Gs-tail chimeras redirect coupling to an IP1 readout in Gq/11-deficient cells; this is not native Gi/Gs second-messenger measurement. Separate TRUPATH assays address Gi1, Gi3 and Gq. The authors report no detectable CaSR-induced Gs activity in HEK293T or MCF7, although that method paragraph names a Gq donor, an unresolved internal description ambiguity. Surface-expression controls and calcium-dependent FRET-background subtraction are explicit. No universal physiological Gs claim is justified. Retain the curator's calcium-regulatory assertion in the context of receptor-dependent calcium signaling and feedback; this is not evidence that CASR itself is a calcium channel, pump or intracellular buffer.

Summary: Receptor activation contributes to regulation of intracellular calcium responses.

Reason: The complete abstract reports human CaSR in HEK293 cells, PKC modulators, phosphorylation-site mutants and in-vitro phosphorylation identifying T888 as a major site. It supports feedback regulation of receptor-dependent cytosolic calcium responses; CASR is the kinase substrate, not the kinase. The cache is abstract-only. Retain the curator's calcium-regulatory assertion in the context of receptor-dependent calcium signaling and feedback; this is not evidence that CASR itself is a calcium channel, pump or intracellular buffer.

Summary: The electronic calcium-regulatory assertion is corroborated by human signaling assays.

Reason: Human CaSR-dependent cytosolic calcium responses and phosphorylation feedback support this broad homeostatic signaling role. The annotation is not equated with direct ion transport or with systemic serum-calcium homeostasis.

Summary: The activating human receptor variant supports calcium-regulatory signaling.

Reason: PubMed and the complete cached abstract identify the human Glu128Ala hypocalcemia study, with increased calcium-evoked inositol-trisphosphate signaling in Xenopus oocytes. This supports altered receptor signaling. Complete primary text was not retrieved; the ossification assertion remains unresolved rather than being rejected from the abstract. The broad regulatory role is independently supported by human CaSR calcium-response experiments, so this established function is retained with curator deference rather than rejecting an abstract-only historical source.

Summary: CASR initiates a G protein-coupled signaling pathway.

Reason: Selected complete structural, ligand-binding, mutational and cellular-assay passages were read. Human extracellular-domain constructs were expressed in insect cells, whereas full-length human receptors were tested in HEK293 cells with surface-expression controls, IP1 and calcium readouts. Scintillation proximity directly demonstrated tryptophan binding; anomalous diffraction supported calcium-binding sites. The paper interprets amino acids as agonists, but later controlled-membrane work distinguishes positive allosteric modulation. Amino-acid binding remains supported irrespective of this activation-model dispute. Ligand sensing and downstream IP1/calcium responses support the receptor-mediated signaling role.

Summary: Conserved receptor domains correctly predict GPCR signaling.

Reason: The domain transfer agrees with direct human CASR signaling and coupling experiments and does not require a new process assertion.

Summary: Human CASR transduces extracellular calcium into intracellular signaling.

Reason: The complete abstract reports a de novo heterozygous R551K variant in cis with A986S in one child with neonatal severe hyperparathyroidism, later mild hypercalcemia, and reduced calcium sensitivity in HEK293 cells. It supports receptor signaling and localization; this family-specific presentation does not redefine the usual recessive severe-disease association. The cache is abstract-only. The variant perturbation supports receptor participation in GPCR signaling; a disease phenotype alone is not being substituted for pathway participation.

Summary: Human CASR transduces extracellular calcium into intracellular signaling.

Reason: The complete abstract reports Q459R in a consanguineous family, mild hypercalcemia in homozygotes, largely normal heterozygotes, and reduced signaling despite cell-surface expression. This is a particular allele/family with apparent recessive mild disease, not a universal inheritance rule. The cache is abstract-only. The variant perturbation supports receptor participation in GPCR signaling; a disease phenotype alone is not being substituted for pathway participation.

Summary: Human CASR transduces extracellular calcium into intracellular signaling.

Reason: The complete abstract reports reduced inositol-phosphate signaling by human T550I CaSR in COS7 cells and an intermediate cotransfection response. It supports GPCR signaling; dominant-negative interpretation remains qualified. The cache is abstract-only. The variant perturbation supports receptor participation in GPCR signaling; a disease phenotype alone is not being substituted for pathway participation.

Summary: Human CASR transduces extracellular calcium into intracellular signaling.

Reason: The complete abstract reports Q681R and P221L in hypocalcemic families and functional testing of Q681R in HEK293 cells, with increased calcium sensitivity despite similar expression and surface targeting. It supports receptor localization and signaling. The cache is abstract-only. The variant perturbation supports receptor participation in GPCR signaling; a disease phenotype alone is not being substituted for pathway participation.

Summary: Human CASR transduces extracellular calcium into intracellular signaling.

Reason: The complete abstract reports human N802I and N802S CaSR in COS7 cells, MAPK signaling and allosteric modulation. N802I showed ligand-independent activity whereas N802S was inactivating. These are variant-dependent receptor phenotypes, not universal constitutive signaling. The cache is abstract-only. The variant perturbation supports receptor participation in GPCR signaling; a disease phenotype alone is not being substituted for pathway participation.

Summary: Human CASR transduces extracellular calcium into intracellular signaling.

Reason: The complete abstract reports gain- and loss-of-function human CaSR variants, calcium-dependent MAPK responses, surface-expression comparisons and rescue by allosteric modulators. It supports receptor signaling. The cache is abstract-only; assay details not stated in the abstract are not inferred. The variant perturbation supports receptor participation in GPCR signaling; a disease phenotype alone is not being substituted for pathway participation.

Summary: Human CASR transduces extracellular calcium into intracellular signaling.

Reason: The complete abstract reports Myc-tagged human CaSR expression in HEK293 cells, absent detectable E707V expression and reduced signaling sensitivity for G774S, with additional family screening. This supports receptor signaling and the tested localization observations, not a conclusion that all hypercalcemic families have CASR variants. The cache is abstract-only. The variant perturbation supports receptor participation in GPCR signaling; a disease phenotype alone is not being substituted for pathway participation.

Summary: Human CASR transduces extracellular calcium into intracellular signaling.

Reason: Selected complete Results, Methods and Discussion passages show Myc-tagged human T972M CaSR in HEK293 cells, wild-type and F351V controls, altered mature glycosylation and reduced calcium-evoked ERK phosphorylation. The father/son hypercalciuric presentation is an atypical family-specific finding. Tissue-selective effects on parathyroid versus kidney are an interpretation rather than directly measured tissue signaling. The variant perturbation supports receptor participation in GPCR signaling; a disease phenotype alone is not being substituted for pathway participation.

Summary: Human CASR transduces extracellular calcium into intracellular signaling.

Reason: The complete abstract reports human P136L CaSR in HEK293 cells, surface localization, increased intracellular-calcium and MAPK responses, and segregation with hypocalcemia in a family. This supports the tested receptor localization and signaling. The cache is abstract-only. The variant perturbation supports receptor participation in GPCR signaling; a disease phenotype alone is not being substituted for pathway participation.

Summary: Human CASR transduces extracellular calcium into intracellular signaling.

Reason: The complete abstract reports human G571W CaSR in COS7 cells, surface expression comparable to wild type and reduced Fura-2 calcium responses. This supports receptor signaling and localization, with no claim to have inspected the complete imaging controls. The cache is abstract-only. The variant perturbation supports receptor participation in GPCR signaling; a disease phenotype alone is not being substituted for pathway participation.

Summary: Human CASR transduces extracellular calcium into intracellular signaling.

Reason: The complete abstract reports human family variant screening and Xenopus oocyte functional tests, with defective calcium responses for three of four tested mutant receptors. It supports receptor signaling while preserving variant-specific differences. The cache is abstract-only. The variant perturbation supports receptor participation in GPCR signaling; a disease phenotype alone is not being substituted for pathway participation.

Summary: Human CASR transduces extracellular calcium into intracellular signaling.

Reason: The complete abstract reports eight human CaSR variants expressed in HEK293 cells, calcium/gadolinium responses, glycosylation and surface-expression differences. It supports receptor signaling and localization. Trafficking versus coupling defects are interpreted within each mutant context. The cache is abstract-only. The variant perturbation supports receptor participation in GPCR signaling; a disease phenotype alone is not being substituted for pathway participation.

Summary: Human CASR transduces extracellular calcium into intracellular signaling.

Reason: The complete abstract reports eleven human CaSR variants expressed in HEK293 cells with altered extracellular-calcium response curves corresponding to loss- or gain-of-function phenotypes. This supports receptor signaling. The cache is abstract-only. The variant perturbation supports receptor participation in GPCR signaling; a disease phenotype alone is not being substituted for pathway participation.

Summary: Human CASR transduces extracellular calcium into intracellular signaling.

Reason: The complete abstract reports cloning of a 1078-residue human parathyroid calcium-sensing receptor, a rare insertion-containing transcript and functional cation responses in Xenopus oocytes. This supports receptor function and calcium sensing. A complete primary body was not retrieved, and organismal chemosensory behavior cannot be adjudicated from the abstract alone. The receptor-expression experiment supports participation in GPCR signaling through functional cation responses.

Summary: CASR can engage Gi-linked signaling that inhibits adenylate cyclase.

Reason: The complete abstract and selected complete Results/Methods paragraphs were read. Two complementary cellular BRET approaches primarily support Gi/o and Gq/11 activation, with receptor surface-expression controls. Human receptor constructs include a 20-894 truncation; structural preparations additionally use GABAB-derived tails, tethering and engineered G proteins. These experiments support receptor coupling in the tested systems, not a universal native-tissue G-protein preference or a direct cAMP measurement. Gi engagement is directly supported, whereas the adenylate-cyclase step is an established pathway interpretation rather than a direct cAMP endpoint in the inspected assays. Retain the curator assertion with that distinction and without imposing one G-protein preference on all tissues.

Summary: CASR can engage Gi-linked signaling that inhibits adenylate cyclase.

Reason: The complete abstract and selected complete construct/functional Methods paragraphs were read. Structures use truncated human receptor and dominant-negative or mini/chimeric G proteins, whereas cellular assays use full-length receptor. Gi/Gs-tail chimeras redirect coupling to an IP1 readout in Gq/11-deficient cells; this is not native Gi/Gs second-messenger measurement. Separate TRUPATH assays address Gi1, Gi3 and Gq. The authors report no detectable CaSR-induced Gs activity in HEK293T or MCF7, although that method paragraph names a Gq donor, an unresolved internal description ambiguity. Surface-expression controls and calcium-dependent FRET-background subtraction are explicit. No universal physiological Gs claim is justified. Gi engagement is directly supported, whereas the adenylate-cyclase step is an established pathway interpretation rather than a direct cAMP endpoint in the inspected assays. Retain the curator assertion with that distinction and without imposing one G-protein preference on all tissues.

Summary: Gi-linked inhibition of adenylate cyclase is independently supported in human CASR.

Reason: Mammalian orthology and combined electronic evidence agree with human coupling studies. G-protein selection depends on receptor and cellular context; this does not imply exclusive Gi coupling.

Summary: CASR drives the phospholipase C-activating GPCR pathway.

Reason: Selected complete cryo-EM interpretation, construct and cellular-assay passages were read. Full-length human CaSR with substituted signal sequence/tags was expressed in insect cells; HEK293T mutant assays measured IP1 with surface-expression controls. Tryptophan closes the Venus flytrap domain but does not alone complete transmembrane activation; calcium and amino acids cooperate in the authors' model. Ambient ligands and conformational intermediates limit absolute ligand-sufficiency conclusions. Gq/11 engagement and phosphoinositide readouts support the receptor's upstream signaling role; CASR is not itself phospholipase C.

Summary: CASR drives the phospholipase C-activating GPCR pathway.

Reason: The complete abstract and selected complete Results/Methods paragraphs were read. Two complementary cellular BRET approaches primarily support Gi/o and Gq/11 activation, with receptor surface-expression controls. Human receptor constructs include a 20-894 truncation; structural preparations additionally use GABAB-derived tails, tethering and engineered G proteins. These experiments support receptor coupling in the tested systems, not a universal native-tissue G-protein preference or a direct cAMP measurement. Gq/11 engagement and phosphoinositide readouts support the receptor's upstream signaling role; CASR is not itself phospholipase C.

Summary: CASR drives the phospholipase C-activating GPCR pathway.

Reason: The complete abstract and selected complete construct/functional Methods paragraphs were read. Structures use truncated human receptor and dominant-negative or mini/chimeric G proteins, whereas cellular assays use full-length receptor. Gi/Gs-tail chimeras redirect coupling to an IP1 readout in Gq/11-deficient cells; this is not native Gi/Gs second-messenger measurement. Separate TRUPATH assays address Gi1, Gi3 and Gq. The authors report no detectable CaSR-induced Gs activity in HEK293T or MCF7, although that method paragraph names a Gq donor, an unresolved internal description ambiguity. Surface-expression controls and calcium-dependent FRET-background subtraction are explicit. No universal physiological Gs claim is justified. Gq/11 engagement and phosphoinositide readouts support the receptor's upstream signaling role; CASR is not itself phospholipase C.

Summary: Rat orthology transfers a PLC-linked pathway corroborated in human cells.

Reason: Human CASR IP1 signaling and Gq coupling independently support the pathway. This is a conserved receptor output, not a claim of direct phospholipid hydrolysis by CASR.

Summary: The JNK cascade assertion requires source-specific evidence.

Reason: The specific rat cell model and JNK activation mechanism are unresolved; generic GPCR signaling does not establish this branch.

Summary: The chemosensory behavior assertion requires source-specific evidence.

Reason: The accessible human receptor-cloning abstract demonstrates cellular calcium sensing, not an organismal behavioral endpoint. The complete primary text was not retrieved, so the historical TAS assertion remains unresolved rather than being declared miscited.

Summary: The positive regulation of cell population proliferation assertion requires source-specific evidence.

Reason: The direction and cell-type dependence of proliferation cannot be inferred from receptor expression or generic ERK signaling without the donor experiment.

Summary: The anatomical structure morphogenesis assertion requires source-specific evidence.

Reason: The accessible human variant-study abstract establishes disturbed calcium sensing and systemic disease. It does not resolve a direct morphogenetic mechanism; complete primary evidence was not retrieved.

Summary: Cell-surface localization agrees with direct human CASR measurements.

Reason: Human surface-expression assays independently corroborate this broad rat-derived location. It is not a claim that every biosynthetic receptor pool is at the cell surface.

Summary: CASR responds to extracellular metal cations through receptor activation.

Reason: Direct human receptor calcium and gadolinium-response experiments support this broad stimulus-response assertion, independently of the detailed rat donor experiment. The receptor detects cations; it is not itself their transporter.

Summary: The broad membrane annotation can be made more informative.

Reason: The conserved seven-transmembrane topology establishes membrane association, and direct human surface-versus-total measurements establish the plasma membrane as the principal signaling location. This refinement does not exclude intracellular biosynthetic pools.

Proposed replacements: plasma membrane

Summary: The basolateral plasma membrane assertion requires source-specific evidence.

Reason: Plasma-membrane localization is well supported, but the polarized membrane domain and source tissue require the exact donor localization experiment.

Summary: The apical plasma membrane assertion requires source-specific evidence.

Reason: Apical versus basolateral targeting can vary across epithelia. The rat donor localization experiment has not yet been read, so general surface localization does not settle this specific domain.

Summary: The extracellular domain directly binds amino acids, including L-tryptophan.

Reason: Human CaSR extracellular-domain structures and scintillation-proximity binding measurements directly support tryptophan recognition. Whether amino acids are described as co-agonists or positive allosteric modulators under particular calcium conditions does not invalidate binding. No amino-acid transporter or calcium-independent agonist role is inferred.

Summary: The protein kinase binding assertion requires source-specific evidence.

Reason: CASR phosphorylation and kinase-dependent signaling do not alone establish a kinase-binding molecular function. The exact rat interaction assay and kinase partner remain unresolved.

Summary: The axon assertion requires source-specific evidence.

Reason: The rat donor neuronal localization experiment and its compartment resolution remain unresolved; general nervous-system expression is insufficient.

Summary: The positive regulation of insulin secretion assertion requires source-specific evidence.

Reason: Insulin secretion is a cell-type-specific endocrine output. Its direction and CASR-dependent mechanism require the donor study, which has not been independently read.

Summary: The bile acid secretion assertion requires source-specific evidence.

Reason: The particular hepatobiliary experiment and the role of CASR in secretion remain unresolved; general calcium signaling is not a substitute.

Summary: The response to hepatocyte growth factor assertion requires source-specific evidence.

Reason: The donor response may concern expression, signaling or a downstream phenotype. Those alternatives have not been resolved from a primary experiment.

Summary: The vasodilation assertion requires source-specific evidence.

Reason: Vascular effects of calcium sensing depend on cell type and preparation; the donor experiment is needed to establish this directional response.

Summary: The presynaptic membrane assertion requires source-specific evidence.

Reason: Presynaptic localization requires compartment-specific evidence beyond general surface expression. The exact donor imaging or fractionation study remains unresolved.

Summary: CASR forms homodimers as part of receptor assembly.

Reason: The complete abstract reports surface localization of wild-type receptor, ER retention of R66H, R66C and N583X mutants, and FRET evidence for wild-type and R66H/R66C dimers. Dimerization is necessary but not sufficient for efficient export in this experiment. The cache is abstract-only, so the full imaging and FRET controls were not independently inspected. Homodimerization is an assembly property of the receptor, not a separate core enzymatic function.

Summary: The extracellular receptor forms a structurally resolved homodimer.

Reason: Selected complete structural, ligand-binding, mutational and cellular-assay passages were read. Human extracellular-domain constructs were expressed in insect cells, whereas full-length human receptors were tested in HEK293 cells with surface-expression controls, IP1 and calcium readouts. Scintillation proximity directly demonstrated tryptophan binding; anomalous diffraction supported calcium-binding sites. The paper interprets amino acids as agonists, but later controlled-membrane work distinguishes positive allosteric modulation. Amino-acid binding remains supported irrespective of this activation-model dispute. Dimer formation and ligand-dependent interface rearrangement are intrinsic to receptor function.

Summary: The neuronal cell body assertion requires source-specific evidence.

Reason: The specific rat neuronal localization evidence has not been inspected, so the compartment-level transfer remains unresolved.

Summary: The axon terminus assertion requires source-specific evidence.

Reason: Axon-terminal targeting is more specific than membrane localization and requires the donor compartment-level experiment.

Summary: The transmembrane transporter binding assertion requires source-specific evidence.

Reason: CASR can regulate ion transport without binding a transporter. The transferred physical interaction and exact transporter partner remain unresolved.

Summary: The positive regulation of vasoconstriction assertion requires source-specific evidence.

Reason: A directional vascular effect cannot be generalized from calcium sensing. The particular donor cell type and functional assay need inspection, especially because other contexts can support dilation.

Summary: The branching morphogenesis of an epithelial tube assertion requires source-specific evidence.

Reason: The exact donor developmental study and receptor contribution to branching remain unresolved; a systemic calcium phenotype does not establish this process.

Summary: The positive regulation of chemotaxis assertion requires source-specific evidence.

Reason: The source-specific cell type, direction of migration and receptor perturbation have not yet been resolved from the rat donor experiment.

Summary: A response to extracellular calcium is intrinsic to CASR signaling.

Reason: Direct human binding and signaling measurements independently support this broad rat-derived response annotation. The response is distinguished from calcium import through a channel.

Summary: CASR regulates calcium handling through a conserved receptor-signaling mechanism.

Reason: The PAINT assertion is consistent with calcium-sensing control of endocrine and renal calcium handling. It represents a phylogenetic judgment, not a pairwise donor-count argument. CASR regulates transport by signaling rather than transporting calcium itself.

Summary: The fat pad development assertion requires source-specific evidence.

Reason: The donor developmental endpoint must be distinguished from altered CASR expression during adipose growth or dietary responses. Primary evidence remains unresolved.

Summary: CASR can positively regulate ERK signaling in receptor-expression assays.

Reason: The rat-derived assertion is independently corroborated by calcium-evoked ERK1/2 phosphorylation in HEK293 cells expressing human CASR, with wild-type and receptor-mutant comparisons. This context-dependent signaling branch is retained outside the core calcium-sensing summary.

Summary: The cellular response to vitamin D assertion requires source-specific evidence.

Reason: A change in receptor expression can be a response annotation but is not necessarily a receptor-mediated vitamin D function. The donor experiment has not been independently assessed.

Summary: The cellular response to glucose stimulus assertion requires source-specific evidence.

Reason: The source-specific response and its direction are unresolved; calcium signaling or pancreatic expression alone does not establish the annotated glucose response.

Summary: The cellular response to low-density lipoprotein particle stimulus assertion requires source-specific evidence.

Reason: The donor expression or signaling endpoint needs inspection; the response must not be confused with CASR acting as an LDL receptor.

Summary: The cellular response to hypoxia assertion requires source-specific evidence.

Reason: The donor oxygen-response experiment and its cellular context remain unresolved; ischemia and hypoxia are not interchangeable assertions.

Summary: The response to fibroblast growth factor assertion requires source-specific evidence.

Reason: The original donor response endpoint has not been assessed. Generic mitogenic signaling or receptor expression is insufficient to establish the specific stimulus.

Summary: The positive regulation of calcium ion import assertion requires source-specific evidence.

Reason: An increase in cytosolic calcium can arise from intracellular release rather than plasma-membrane import. The donor transport assay is needed to distinguish these possibilities.

Summary: The glutamatergic synapse assertion requires source-specific evidence.

Reason: The mouse source supports a synapse-specific location that cannot be established solely from GPCR family membership or general neuronal expression. Exact donor evidence remains unresolved.

Summary: The regulation of presynaptic membrane potential assertion requires source-specific evidence.

Reason: The mouse neuronal physiology experiment and mechanism remain unresolved. General calcium-dependent signaling does not establish presynaptic membrane-potential regulation.

Summary: CASR promotes NLRP3 inflammasome activation in a defined myeloid context.

Reason: Human monocyte and CaSR-deficient THP-1 experiments, together with mouse myeloid Casr deletion, support an upstream role in calcium/phosphate-dependent calciprotein-particle uptake and inflammatory activation. NLRP3 dependence and ASC-speck methodology support this regulatory process. The effect is partial and context-dependent: CASR is neither an inflammasome subunit nor the sole route to activation. The original evidence code is preserved.

Summary: CASR promotes NLRP3 inflammasome activation in a defined myeloid context.

Reason: Human monocyte and CaSR-deficient THP-1 experiments, together with mouse myeloid Casr deletion, support an upstream role in calcium/phosphate-dependent calciprotein-particle uptake and inflammatory activation. NLRP3 dependence and ASC-speck methodology support this regulatory process. The effect is partial and context-dependent: CASR is neither an inflammasome subunit nor the sole route to activation. The electronic/sequence transfer is corroborated by direct human evidence.

Summary: CASR promotes NLRP3 inflammasome activation in a defined myeloid context.

Reason: Human monocyte and CaSR-deficient THP-1 experiments, together with mouse myeloid Casr deletion, support an upstream role in calcium/phosphate-dependent calciprotein-particle uptake and inflammatory activation. NLRP3 dependence and ASC-speck methodology support this regulatory process. The effect is partial and context-dependent: CASR is neither an inflammasome subunit nor the sole route to activation. The electronic/sequence transfer is corroborated by direct human evidence.

Summary: The cellular response to peptide assertion requires source-specific evidence.

Reason: The broad peptide-response transfer requires its original rat stimulus and endpoint. It is not automatically established by the existence of synthetic peptide receptor modulators.

Summary: The rat donor assay supports receptor-mediated activation of chloride channels, rather than assigning their transport step to human CASR.

Reason: GO:1902476 denotes chloride movement across a membrane, under chloride and inorganic-anion transmembrane transport. GO_REF:0000107 transfers experimentally curated donor assertions through Ensembl orthology; the rat source is not uncurated. The dated official Casr donor graph links this rat IDA assertion to PMID:7816802. In the independently read original Results and Figure 3 caption, rat kidney receptor RNA expressed in Xenopus oocytes produces calcium-activated chloride currents after polyvalent-cation stimulation, whereas water-injected controls do not. Persistence of the response without extracellular calcium supports signaling through intracellular calcium release to the oocyte chloride channels. This positive experiment establishes an upstream receptor-dependent channel response, not a chloride-translocation step performed by CASR. Transferring that readout as human CASR involvement in chloride transport overextends the demonstrated assay role. This is not a universal rule that only pore proteins can participate in transport, a negative experiment on human CASR, or a declaration that the donor curator made an error. The established receptor-signaling annotations are retained; a particular human chloride-transport regulatory subtype is not added without its relevant assay.

Summary: Positive regulation of intracellular signaling follows directly from receptor activation.

Reason: The broad ARBA assertion is consistent with human ligand-dependent G-protein, phosphoinositide and calcium signaling assays. It is retained as an existing assertion without adding another redundant core process.