id: MODULE:calcium_sensing_receptor_signaling title: Calcium-sensing receptor signaling — extracellular calcium activation of CaSR, Gq/11-phospholipase C and Gi/o-adenylyl cyclase coupling, AP2-dependent endocytic signalling, PKC feedback, and GRK/beta-arrestin desensitization description: >- The calcium-sensing receptor (CaSR) is a class C G protein-coupled receptor that detects the concentration of extracellular calcium and sets the body's calcium set point. It is most abundant in the parathyroid glands, where its activation suppresses parathyroid hormone secretion, and in the kidney, where it regulates calcium reabsorption. CaSR is an obligate disulfide-linked homodimer; calcium ions bind cooperatively in the Venus flytrap domains of its large extracellular region, closing them and driving an asymmetric rearrangement of the seven-transmembrane domains. The active receptor couples to G alpha q/11, which activates phospholipase C beta to produce inositol trisphosphate (release of stored calcium) and diacylglycerol (protein kinase C), and to G alpha i/o, which inhibits adenylyl cyclase and lowers cAMP. Loss-of-function mutations in CASR, in GNA11 (G alpha 11) or in AP2S1 (the sigma 2 subunit of the clathrin adaptor AP-2, which mediates CaSR endocytosis and sustained signalling) each cause familial hypocalciuric hypercalcaemia, and gain-of-function CASR and GNA11 mutations cause autosomal dominant hypocalcaemia. Protein kinase C phosphorylation of the receptor tail feeds back to blunt calcium mobilization, and G protein-coupled receptor kinases and beta-arrestins desensitize the receptor. status: DRAFT scope: CONCRETE references: - id: PMID:8255296 title: Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid. reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- PubMed-verified (Brown et al., Nature 1993). Abstract only. Cloning of CaSR; the native sensor couples through phosphoinositide turnover and cytosolic calcium to PTH secretion. - id: PMID:27434672 title: Structural mechanism of ligand activation in human calcium-sensing receptor. reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- Full text cached (Geng et al., eLife 2016); source of CASR IDA rows for calcium ion binding and detection of calcium ion. Cited for Ca2+ as principal agonist and the range of G protein couplings. - id: PMID:38632411 title: Promiscuous G-protein activation by the calcium-sensing receptor. reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- Full text cached (Zuo et al., Nature 2024); CaSR-Gq and CaSR-Gi structures; source of CASR IDA rows for GO:0007193 and GO:0007200. - id: PMID:38326620 title: Allosteric modulation and G-protein selectivity of the Ca(2+)-sensing receptor. reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- Full text cached (He et al., Nature 2024); CaSR coupling to Gi versus Gq in nanodiscs. - id: PMID:23802516 title: Mutations affecting G-protein subunit α11 in hypercalcemia and hypocalcemia. reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- PubMed-verified (Nesbit et al., NEJM 2013); full text cached. GNA11 loss-of-function causes FHH2 and gain-of-function causes ADH2, by changing cell sensitivity to extracellular calcium. - id: PMID:23222959 title: Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3. reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- Full text cached (Nesbit et al., Nat Genet 2013). AP2S1 Arg15 mutations reduce CaSR endocytosis and cell sensitivity to extracellular calcium. - id: PMID:9694886 title: Protein kinase C phosphorylation of threonine at position 888 in Ca2+o-sensing receptor (CaR) inhibits coupling to Ca2+ store release. reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: >- Abstract only (Bai et al., JBC 1998). PKC phosphorylation of CaSR Thr888 inhibits receptor-evoked calcium release. - id: PMID:15637145 title: Beta-arrestin- and G protein receptor kinase-mediated calcium-sensing receptor desensitization. reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- PubMed-verified (Pi et al., Mol Endocrinol 2005; RGD diagram reference RGD:7207060). Abstract only. GRK4 and GRK2 desensitize CaSR; beta-arrestin2 null mice show altered PTH responses. evidence: - source_id: PW:0001141 title: calcium signaling pathway via the calcium-sensing receptor statement: >- The module boundary follows the RGD diagram for this Pathway Ontology term: Ca2+, calcimimetics and calcilytics associated with Casr; Casr feeding the Galphaq, Galphai and Galpha12/13 family G protein pathways, giving increased DAG/IP3 via PLC activation (and PKC signalling) and inhibition of adenylyl cyclases/decreased cAMP; GRKs acting negatively on Casr, with Arrb1 and Arrb2 associated with it; RGS proteins acting negatively on the three G protein pathways; Flna associated with Casr; and Casr acting negatively on PTH secretion and the parathyroid hormone signaling pathway. Derived through projects/RGD_PATHWAY_ONTOLOGY (pathways/PW_0001141.yaml). - source_id: GO:0071277 title: cellular response to calcium ion statement: >- The closest GO process; GO has no calcium-sensing receptor signaling pathway term, and this term covers every cellular response to calcium (see notes). notes: >- Derived from the RGD Pathway Ontology diagram PW:0001141 (12 RGD-curated human genes) through the RGD_PATHWAY_ONTOLOGY project, where it sits in the no_specific_go_term tier. GO term search. The go-basic release used for validation (2026-07-26) was searched again for calcium-sensing, extracellular calcium, calcium ion sensing and calcium response terms. There is no CaSR signaling pathway term and no receptor-specific molecular function term (no "calcium-sensing receptor activity"). The live terms are GO:0071277 cellular response to calcium ion (module concept, as on the project page), GO:0005513 detection of calcium ion (synonym calcium ion sensing), which CASR carries by IDA and as a CASR review core process and which is used on the receptor annoton, and the generic G protein routes GO:0007200 and GO:0007193, also CASR IDA rows. The two "calcium-mediated signaling using extracellular/intracellular calcium source" terms are obsolete. A CaSR signaling pathway term is requested in proposed_new_terms. Molecular functions come from experimental GOA rows or gene review core functions: CASR GO:0004930 G protein-coupled receptor activity (IDA; CASR review core); GNA11 and GNAQ GO:0003925 G protein activity (IDA; review core); GNAI1 and GNAI2 GO:0003925 (IDA; review core); AP2S1 GO:0035615 clathrin-cargo adaptor activity (TAS, accepted in the AP2S1 review, whose core functions carry no molecular function); GRK2 GO:0004703 (IDA; review core); ARRB1/ARRB2 GO:0030674 protein-macromolecule adaptor activity (IDA), as in the sibling pth_receptor_signaling module. The ligand, extracellular Ca2+, is a chemical and not an annoton; calcimimetics (positive allosteric modulators such as cinacalcet) and calcilytics are pharmacology, recorded here only. Shared steps by reference. The Gq/11 route reuses the phospholipase C beta step of modules/gpcr_plc_calcium_pkc_signaling.yaml by module_ref, as pth_receptor_signaling does, and the PKC step of the same module is referenced for the feedback loop. The G alpha 11/q annoton is kept local because GNA11 is a disease gene of this pathway (FHH2/ADH2). The Gi/o route has no generic module, so the G alpha i annoton is local and its target, the adenylyl cyclase step of modules/gpcr_camp_pka_signaling.yaml, is referenced and connected with NEGATIVELY_REGULATES. Downstream PKA, IP3 receptor calcium release and PTH secretion are outside the module. Added genes. GNA11, GNAQ, GNAI1, GNAI2 and AP2S1 are not on RGD's curated list for PW:0001141 (RGD represents the G protein steps as links to PW:0000229 and PW:0000228) but the coupling steps cannot be modelled without the G alpha subunits, and GNA11 and AP2S1 are the FHH2 and FHH3 genes that regulate CaSR signalling directly (PMID:23802516, PMID:23222959). AP2S1 is modelled as a regulator that sustains signalling: FHH3 mutations reduce CaSR endocytosis and decrease cell sensitivity to extracellular calcium, and loss of the CaSR dileucine motif that AP2 sigma 2 recognises also reduces intracellular signalling, so AP2-mediated endocytosis supports rather than ends the response here. Termination and feedback. GRK4 and GRK2 desensitize CaSR and beta-arrestin2 matters in vivo (PMID:15637145); GRK3, also on the RGD list, has no specific CaSR evidence in the cached literature and is mentioned only. PKC phosphorylation of Thr888 blunts receptor-evoked calcium release (PMID:9694886). The RGS proteins on the RGD list (RGS2, RGS4, RGS5, RGS12) act on the G alpha subunits generally and are not modelled as parts; the RGD record notes that several inhibit CaSR signalling, but no cached paper was found to ground a specific one. Filamin A (FLNA) and RHOA, the G12/13-Rho route, Gs coupling in breast cancer cells, and the ERK/MAPK outputs (RGD links PW:0000230, PW:0000105, PW:0000102) are out of scope; FLNA binds the receptor tail and scaffolds Rho signalling (RGD record text) and belongs with a Rho module. GO-CAM grounding. CASR is linked to its two human models: the Gq model gomodel:67c10cc400004380 (CASR, GNAQ, PLCB3) and the Gi model gomodel:67c10cc400004342 (CASR, GNAI1, ADCY6). PLCB3 and ADCY6 are in the referenced generic modules. GNA11 is not in either CASR model, which uses GNAQ. The GRK2 and arrestin annotons are linked, as in pth_receptor_signaling, to the desensitization model gomodel:67f85f2b00004426 built for C5AR1 (the seed's best_gocam lead): gene and function match but not the receptor. No cached GO-CAM covers AP2S1 with CaSR. GRK4, ARRB1 and ARRB2 have no gene review yet in this repository's genes/human tree, which is curation follow-up for the project plan. proposed_new_terms: - proposed_name: calcium-sensing receptor signaling pathway proposed_definition: >- A G protein-coupled receptor signaling pathway initiated by extracellular calcium ions binding to the calcium-sensing receptor (CaSR) on the surface of a target cell, and ending with the regulation of a downstream cellular process. justification: >- GO has no CaSR signaling pathway term. The module concept uses GO:0071277 cellular response to calcium ion, and the receptor annoton uses the generic G protein routes GO:0007200 and GO:0007193. proposed_parent: id: GO:0007186 label: G protein-coupled receptor signaling pathway supported_by: - reference_id: PMID:27434672 supporting_text: The general consensus is that the principal agonist of CaSR is extracellular Ca2+ - reference_id: PMID:38632411 supporting_text: In parathyroid and kidney, CaSR signals through Gq/11 and Gi/o module: id: calcium_sensing_receptor_signaling label: Calcium-sensing receptor signaling module_type: SIGNALING_PATHWAY concepts: - preferred_term: cellular response to calcium ion term: id: GO:0071277 label: cellular response to calcium ion description: >- Broad GO process; GO has no calcium-sensing receptor signaling pathway term. The module is the CaSR-initiated share of the cellular response to extracellular calcium. context: taxa: - preferred_term: Homo sapiens term: id: NCBITaxon:9606 label: Homo sapiens description: >- Members are grounded on the human proteins; the diagram is RGD's rat curation and the pathway is conserved across vertebrates. cellular_components: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane description: CaSR, its G proteins, GRKs and arrestins act at the plasma membrane. parts: - order: 1 role: CaSR activation by extracellular calcium and G protein coupling node: id: casr_receptor label: CaSR senses extracellular calcium and couples to Gq/11 and Gi/o module_type: REGULATORY_STEP description: >- Extracellular Ca2+ binds the Venus flytrap domains of the CaSR homodimer; the active receptor acts as a guanine nucleotide exchange factor for G alpha q/11 and G alpha i/o. annotons: - id: casr_gpcr label: CaSR G protein-coupled receptor activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CASR term: id: UniProtKB:P41180 label: Extracellular calcium-sensing receptor function: preferred_term: G protein-coupled receptor activity term: id: GO:0004930 label: G protein-coupled receptor activity processes: - preferred_term: detection of calcium ion term: id: GO:0005513 label: detection of calcium ion - preferred_term: phospholipase C-activating G protein-coupled receptor signaling pathway term: id: GO:0007200 label: phospholipase C-activating G protein-coupled receptor signaling pathway - preferred_term: adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway term: id: GO:0007193 label: adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Class C dimeric GPCR whose principal agonist is extracellular Ca2+; the hub of the module and the target of AP2 endocytosis, PKC feedback and GRK/arrestin desensitization. evidence: - source_id: PMID:8255296 statement: >- The parathyroid cell-surface Ca2+ sensor couples through phosphoinositide turnover and cytosolic Ca2+ to regulation of PTH secretion. supporting_text: >- couples by changes in phosphoinositide turnover and cytosolic Ca2+ to regulation of parathyroid hormone secretion - source_id: PMID:27434672 statement: Extracellular Ca2+ is the principal CaSR agonist. supporting_text: >- The general consensus is that the principal agonist of CaSR is extracellular Ca2+ - source_id: PMID:38632411 statement: In parathyroid and kidney CaSR signals through Gq/11 and Gi/o. supporting_text: In parathyroid and kidney, CaSR signals through Gq/11 and Gi/o - source_id: PMID:38326620 statement: The receptor couples selectively to Gi and Gq through distinct interfaces. supporting_text: >- Selective Gi and Gq coupling by the receptor is achieved through substantial rearrangements of intracellular loop 2 and the C terminus gocam_associations: - model: gomodel:67c10cc400004380 activity: gomodel:67c10cc400004380/67c10cc400004381 title: CASR-mediated signaling via G-alpha-q (phospholipase c-activating, IP3, DAG) following activation by extracellular calcium (Human). description: Same gene and molecular function (GO:0004930), upstream of GNAQ and PLCB3. - model: gomodel:67c10cc400004342 activity: gomodel:67c10cc400004342/67c10cc400004343 title: CASR-mediated signaling via G-alpha-i (inhibitory), inhibiting adenylate cyclase) following activation by extracellular calcium (Human). description: Same gene and molecular function (GO:0004930), upstream of GNAI1 and ADCY6. variant_sets: - id: casr_g_protein_routes label: CaSR G protein routes axis: G protein class selection: ONE_OR_MORE notes: >- Parathyroid and kidney cells use both routes; G12/13 and (in some cancer cells) Gs coupling are outside the module. variants: - id: casr_gq_route label: Gq/11 route (phospholipase C beta) module_type: REGULATORY_STEP description: CaSR activates G alpha 11 and G alpha q, which stimulate phospholipase C beta. annotons: - id: casr_gna11 label: G alpha 11/q G protein activity participant: selector_type: FAMILY family: preferred_term: G alpha q/11 subunits (GNA11, GNAQ) representative_members: - preferred_term: GNA11 (G alpha 11) term: id: UniProtKB:P29992 label: Guanine nucleotide-binding protein subunit alpha-11 - preferred_term: GNAQ (G alpha q) term: id: UniProtKB:P50148 label: Guanine nucleotide-binding protein G(q) subunit alpha function: preferred_term: G protein activity term: id: GO:0003925 label: G protein activity processes: - preferred_term: phospholipase C-activating G protein-coupled receptor signaling pathway term: id: GO:0007200 label: phospholipase C-activating G protein-coupled receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- G alpha 11 is the CaSR G protein whose loss-of-function causes FHH2 and gain-of-function causes ADH2; G alpha q is its paralog and the subunit used in the CASR GO-CAM. evidence: - source_id: PMID:23802516 statement: CaSR signals through G alpha 11. supporting_text: >- the calcium-sensing receptor, a guanine nucleotide-binding protein (G-protein)-coupled receptor that signals through the G-protein subunit α11 (Gα11) - source_id: PMID:23802516 statement: >- FHH2 GNA11 mutations decrease, and ADH2 mutations increase, the sensitivity of CaSR-expressing cells to extracellular calcium. supporting_text: >- familial hypocalciuric hypercalcemia type 2-associated mutations decreased the sensitivity of cells expressing calcium-sensing receptors to changes in extracellular calcium concentrations, whereas autosomal dominant hypocalcemia type 2-associated mutations increased cell sensitivity gocam_associations: - model: gomodel:67c10cc400004380 activity: gomodel:67c10cc400004380/67c10cc400004383 title: CASR-mediated signaling via G-alpha-q (phospholipase c-activating, IP3, DAG) following activation by extracellular calcium (Human). description: GNAQ with the same molecular function (GO:0003925) and process (GO:0007200). - id: casr_gi_route label: Gi/o route (adenylyl cyclase inhibition) module_type: REGULATORY_STEP description: CaSR activates G alpha i, which inhibits adenylyl cyclase and lowers cAMP. annotons: - id: casr_gnai label: G alpha i G protein activity participant: selector_type: FAMILY family: preferred_term: G alpha i subunits (GNAI1, GNAI2) representative_members: - preferred_term: GNAI1 term: id: UniProtKB:P63096 label: Guanine nucleotide-binding protein G(i) subunit alpha-1 - preferred_term: GNAI2 term: id: UniProtKB:P04899 label: Guanine nucleotide-binding protein G(i) subunit alpha-2 function: preferred_term: G protein activity term: id: GO:0003925 label: G protein activity processes: - preferred_term: adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway term: id: GO:0007193 label: adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Inhibitory G alpha subunits; their GTP-bound form inhibits adenylyl cyclase. evidence: - source_id: PMID:38632411 statement: CaSR forms complexes with Gi as well as Gq. supporting_text: >- We determined structures of CaSR in complex with G proteins from three different subfamilies: Gq, Gi and Gs. gocam_associations: - model: gomodel:67c10cc400004342 activity: gomodel:67c10cc400004342/67c10cc400004345 title: CASR-mediated signaling via G-alpha-i (inhibitory), inhibiting adenylate cyclase) following activation by extracellular calcium (Human). description: GNAI1 with the same molecular function (GO:0003925) and process (GO:0007193), upstream of ADCY6. - order: 2 role: phospholipase C beta produces IP3 and DAG node: id: casr_plc_beta label: Phospholipase C beta produces IP3 and DAG description: >- Included by reference to the PLC beta step of the generic Gq-PLC-calcium-PKC module (the CASR GO-CAM uses PLCB3). module_ref: gpcr_plc_calcium_pkc_signaling#plc_beta_activation - order: 3 role: PKC activation and receptor feedback optional: true node: id: casr_pkc_feedback label: PKC activation feeds back on CaSR description: >- Included by reference to the PKC step of the generic module. DAG-activated PKC phosphorylates CaSR Thr888 and blunts receptor-evoked calcium release. module_ref: gpcr_plc_calcium_pkc_signaling#pkc_activation evidence: - source_id: PMID:9694886 statement: PKC phosphorylation of CaSR Thr888 mediates the inhibition of receptor-evoked calcium mobilization. supporting_text: >- threonine at amino acid position 888 is the major PKC site that mediates the inhibitory effect of PKC activators on Ca2+ mobilization - order: 4 role: adenylyl cyclase inhibition node: id: casr_adenylyl_cyclase label: Adenylyl cyclase (inhibited) description: >- Included by reference to the adenylyl cyclase step of the generic Gs-cAMP-PKA module; here G alpha i inhibits it, lowering cAMP (the CASR Gi GO-CAM uses ADCY6). module_ref: gpcr_camp_pka_signaling#adenylyl_cyclase_activation - order: 5 role: AP2-mediated CaSR endocytosis sustaining signalling (regulation) optional: true node: id: casr_ap2_endocytosis label: AP2 sigma 2 recognition of CaSR for clathrin-mediated endocytosis module_type: REGULATORY_STEP description: >- The AP-2 adaptor, through its sigma 2 subunit, binds the CaSR carboxy-terminal dileucine motif and drives clathrin-mediated endocytosis, which supports sustained signalling and the receptor's sensitivity to extracellular calcium. annotons: - id: casr_ap2s1 label: AP2S1 clathrin-cargo adaptor activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: AP2S1 (AP-2 complex subunit sigma) term: id: UniProtKB:P53680 label: AP-2 complex subunit sigma function: preferred_term: clathrin-cargo adaptor activity term: id: GO:0035615 label: clathrin-cargo adaptor activity targets: - preferred_term: CaSR carboxy-terminal dileucine motif term: id: UniProtKB:P41180 label: Extracellular calcium-sensing receptor processes: - preferred_term: clathrin-dependent endocytosis term: id: GO:0072583 label: clathrin-dependent endocytosis locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- The sigma 2 subunit of the AP-2 clathrin adaptor; FHH3 mutations at Arg15 reduce CaSR endocytosis and signalling. It acts as part of the AP-2 heterotetramer. evidence: - source_id: PMID:23222959 statement: >- FHH3 AP2S1 mutations decrease CaSR-expressing cells' sensitivity to extracellular calcium and reduce CaSR endocytosis. supporting_text: >- AP2S1 mutations decreased the sensitivity of CaSR-expressing cells to extracellular calcium and reduced CaSR endocytosis, probably through loss of interaction with a C-terminal CaSR dileucine-based motif, whose disruption also decreased intracellular signaling. - order: 6 role: receptor desensitization (termination) node: id: casr_termination label: GRK phosphorylation and beta-arrestin desensitization of CaSR module_type: REGULATORY_STEP description: >- GRKs phosphorylate the agonist-occupied receptor and beta-arrestins bind it, uncoupling it from its G proteins; GRK2 additionally disrupts Gq signalling independently of phosphorylation. annotons: - id: casr_grk label: GRK phosphorylation of CaSR participant: selector_type: FAMILY family: preferred_term: G protein-coupled receptor kinases (GRK2, GRK4) representative_members: - preferred_term: GRK2 term: id: UniProtKB:P25098 label: G protein-coupled receptor kinase 2 - preferred_term: GRK4 term: id: UniProtKB:P32298 label: G protein-coupled receptor kinase 4 function: preferred_term: G protein-coupled receptor kinase activity term: id: GO:0004703 label: G protein-coupled receptor kinase activity targets: - preferred_term: CaSR term: id: UniProtKB:P41180 label: Extracellular calcium-sensing receptor processes: - preferred_term: desensitization of G protein-coupled receptor signaling pathway term: id: GO:0002029 label: desensitization of G protein-coupled receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- GRK4 enhances CaSR phosphorylation and arrestin recruitment; GRK2 desensitizes by phosphorylation and by disrupting Gq signalling. evidence: - source_id: PMID:15637145 statement: GRK4 inhibits CaSR signalling by enhancing receptor phosphorylation and beta-arrestin translocation. supporting_text: >- the transfection of GRK4 inhibits CASR signaling by enhancing receptor phosphorylation and beta-arrestin translocation to the CASR - source_id: PMID:15637145 statement: GRK2 desensitizes CaSR by classical and phosphorylation-independent mechanisms. supporting_text: >- overexpression of GRK2 desensitizes CASR by classical mechanisms as well as through phosphorylation-independent mechanisms involving disruption of Galphaq signaling gocam_associations: - model: gomodel:67f85f2b00004426 activity: gomodel:67f85f2b00004426/67f85f2b00004469 title: Desensitization of C5AR1-mediated signaling following phosphorylation by GRK2 or GRK3 (Human). description: >- GRK2 with the same molecular function (GO:0004703) and process (GO:0002029), modelled on C5AR1 rather than CaSR. - id: casr_arrestin label: Beta-arrestin desensitization of CaSR participant: selector_type: FAMILY family: preferred_term: beta-arrestins (ARRB1, ARRB2) representative_members: - preferred_term: ARRB1 (beta-arrestin-1) term: id: UniProtKB:P49407 label: Beta-arrestin-1 - preferred_term: ARRB2 (beta-arrestin-2) term: id: UniProtKB:P32121 label: Beta-arrestin-2 function: preferred_term: protein-macromolecule adaptor activity term: id: GO:0030674 label: protein-macromolecule adaptor activity targets: - preferred_term: CaSR term: id: UniProtKB:P41180 label: Extracellular calcium-sensing receptor processes: - preferred_term: desensitization of G protein-coupled receptor signaling pathway term: id: GO:0002029 label: desensitization of G protein-coupled receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Bind the phosphorylated receptor and block G protein coupling; beta-arrestin2 loss alters the parathyroid response to hypocalcaemia in mice. RGD also links the arrestins to ERK activation, which is outside the module. evidence: - source_id: PMID:15637145 statement: Beta-arrestin2-null mice show lower PTH and an attenuated PTH rise after hypocalcaemia. supporting_text: >- we observed lower circulating PTH levels and an attenuated increase in serum PTH after hypocalcemic stimulation in beta-arrestin2 null mice gocam_associations: - model: gomodel:67f85f2b00004426 activity: gomodel:67f85f2b00004426/67f85f2b00004504 title: Desensitization of C5AR1-mediated signaling following phosphorylation by GRK2 or GRK3 (Human). description: ARRB1 with the same molecular function (GO:0030674), modelled on C5AR1. - model: gomodel:67f85f2b00004426 activity: gomodel:67f85f2b00004426/67f85f2b00004511 title: Desensitization of C5AR1-mediated signaling following phosphorylation by GRK2 or GRK3 (Human). description: ARRB2 with the same molecular function (GO:0030674), modelled on C5AR1. connections: - source: casr_gq_route target: casr_plc_beta connection_type: POSITIVELY_REGULATES description: G alpha q/11-GTP activates phospholipase C beta. - source: casr_plc_beta target: casr_pkc_feedback connection_type: PROVIDES_INPUT_FOR description: Diacylglycerol (with released calcium) activates PKC. - source: casr_pkc_feedback target: casr_receptor connection_type: NEGATIVELY_REGULATES description: PKC phosphorylation of CaSR Thr888 inhibits coupling to calcium store release. - source: casr_gi_route target: casr_adenylyl_cyclase connection_type: NEGATIVELY_REGULATES description: G alpha i-GTP inhibits adenylyl cyclase, lowering cAMP. - source: casr_ap2_endocytosis target: casr_receptor connection_type: POSITIVELY_REGULATES description: >- AP2-dependent endocytosis sustains CaSR signalling; FHH3 mutations that reduce it lower the receptor's sensitivity to extracellular calcium. - source: casr_termination target: casr_receptor connection_type: NEGATIVELY_REGULATES description: GRK phosphorylation and beta-arrestin binding desensitize CaSR.