Cyclic AMP receptor 3 (cAR3, carC) is one of four serpentine seven-transmembrane G protein-coupled cAMP receptors of the social amoeba Dictyostelium discoideum. It is an intermediate-affinity receptor for extracellular cAMP that is induced at early aggregation and reaches maximal expression during the multicellular mound and slug stages. Like its close paralog cAR1 (carA), cAR3 couples through heterotrimeric G proteins (notably Galpha2) to intracellular effectors, triggering activation of adenylyl cyclase (cAMP relay), guanylyl cyclase, actin polymerization and small-GTPase (Rap1) signaling. Through these outputs it mediates chemotaxis toward cAMP and the aggregation of individual cells into a multicellular organism, and it contributes to the developmentally regulated gene-expression program. cAR1 and cAR3 are partially redundant, and cells lacking both receptors are unresponsive to cAMP, whereas single mutants retain substantial signaling. The receptor is a plasma-membrane glycoprotein whose C-terminal cytoplasmic tail can be phosphorylated.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004930 G protein-coupled receptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: cAR3 is a bona fide serpentine (7TM) G protein-coupled receptor of the Dictyostelium cAR family that signals through heterotrimeric G proteins. The phylogenetic inference is correct and consistent with direct experimental evidence. Reason: cAR3 belongs to the cAMP receptor GPCR family and couples to heterotrimeric G proteins, as shown directly by the loss of cAMP responses in car1-/car3- cells and their dependence on Galpha2. The more specific MF is cAMP receptor activity (GO:0001646), but the general GPCR activity term is also correct. Supporting Evidence: PMID:7949426 both interact with the same heterotrimeric G-protein to mediate these and other responses |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: cAR3 is a multi-pass plasma-membrane receptor that senses extracellular cAMP at the cell surface. Plasma-membrane localization is correct and is the site where the receptor is active. Reason: As a cell-surface cAMP receptor with seven transmembrane helices, cAR3 is an integral plasma-membrane protein, consistent with its role in detecting the extracellular chemoattractant. Supporting Evidence: PMID:2722797 four forms of the cell surface receptor |
| GO:0007189 adenylate cyclase-activating G protein-coupled receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: cAR3 activation leads to stimulation of adenylyl cyclase (cAMP relay) via heterotrimeric G proteins, so participation in an adenylate cyclase-activating GPCR signaling pathway is correct. A cAMP-ligand specific child term (GO:0140582) is also annotated and is more precise. Reason: Both cAR1 and cAR3 mediate cAMP relay (adenylyl cyclase activation), which is lost in car1-/car3- cells. The pathway annotation is well supported, though the cAMP-specific term GO:0140582 captures the ligand. Supporting Evidence: PMID:9578623 activation of adenylyl cyclase |
| GO:0004888 transmembrane signaling receptor activity | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: This InterPro2GO annotation is a correct but general parent of the more informative cAMP receptor activity and GPCR activity terms already annotated to cAR3. Reason: The term is technically correct (cAR3 is a transmembrane signaling receptor) but is subsumed by the more specific cAMP receptor activity (GO:0001646) and GPCR activity (GO:0004930) annotations, so it is not the core function. Supporting Evidence: PMID:2722797 four forms of the cell surface receptor |
| GO:0004930 G protein-coupled receptor activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO assignment of GPCR activity from the cAMP receptor domain (IPR000848). Correct and concordant with the IBA and experimental evidence. Reason: cAR3 is a member of the Dictyostelium cAMP GPCR family; the domain-based assignment of GPCR activity is accurate. Supporting Evidence: PMID:7949426 both interact with the same heterotrimeric G-protein to mediate these and other responses |
| GO:0007165 signal transduction | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: A very general biological-process term. cAR3 is a signaling receptor, so this is correct but uninformative relative to the specific GPCR/cAMP signaling pathway terms already present. Reason: Correct at a high level but far too general to represent the core biology; the specific pathway terms (GO:0140582, GO:0007189) are the informative annotations. Supporting Evidence: PMID:9578623 activate common responses at different agonist |
| GO:0007166 cell surface receptor signaling pathway | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Correct general parent term; cAR3 is a cell-surface receptor that transduces an extracellular signal. Subsumed by the more specific GPCR signaling pathway annotations. Reason: Accurate but general; the specific adenylate cyclase-activating GPCR cAMP receptor signaling pathway is the informative term. Supporting Evidence: PMID:2722797 four forms of the cell surface receptor |
| GO:0007186 G protein-coupled receptor signaling pathway | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: cAR3 signals as a GPCR through heterotrimeric G proteins, so this pathway term is correct. It is a general parent of the cAMP-specific and adenylate cyclase-activating child terms already annotated. Reason: Correct but general; the more specific cAMP receptor signaling pathway terms better capture the core function. Supporting Evidence: PMID:7949426 both interact with the same heterotrimeric G-protein to mediate these and other responses |
| GO:0016020 membrane | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: General membrane localization inferred from the multi-pass membrane domain. Correct but subsumed by the more specific plasma membrane annotation. Reason: cAR3 is an integral membrane protein, but plasma membrane (GO:0005886) is the specific, informative location. Supporting Evidence: PMID:2722797 four forms of the cell surface receptor |
| GO:0030552 cAMP binding | IEA GO_REF:0000002 | ACCEPT | Summary: Domain-based (InterPro) inference of cAMP binding, concordant with direct radioligand binding measurements for cAR3. This is a core molecular activity of the receptor. Reason: cAR3 directly binds cAMP, as shown by [3H]cAMP binding studies that measured its affinity states; the InterPro assignment agrees with the experimental data. Supporting Evidence: PMID:1537842 20 and 500 nM for cAR3 |
| GO:0035589 G protein-coupled purinergic nucleotide receptor signaling pathway | IEA GO_REF:0000108 | REMOVE | Summary: This term was assigned by automated inter-ontology logical inference from cAMP receptor activity. Although cAMP is chemically a purine nucleotide, purinergic nucleotide receptor signaling denotes the P1/P2-type receptor systems responding to extracellular ATP/ADP/adenosine. Dictyostelium cAMP chemoattractant signaling is not purinergic signaling in that sense. Reason: The annotation is a mechanical over-propagation from the inter-ontology mapping of cAMP receptor activity to a purinergic pathway. cAR3 is a cAMP chemoattractant receptor, not a purinergic (ATP/adenosine) receptor, so this pathway term mischaracterizes its biology. Supporting Evidence: PMID:7949426 both interact with the same heterotrimeric G-protein to mediate these and other responses |
| GO:1904776 regulation of protein localization to cell cortex | IGI PMID:40934557 The Ras association domain of DydA as a specific reporter of... | KEEP AS NON CORE | Summary: Cortical translocation of the RasG biosensor GFP-RA1:DydA during chemotaxis required cAR1/cAR3 and G-protein signaling, placing cAR3 upstream of protein localization to the cell cortex. This is a valid but downstream regulatory role rather than a core molecular function. Reason: The IGI experiment shows cAR1/cAR3 are required for cortical and leading-edge recruitment of a downstream Ras effector reporter. cAR3 acts upstream of this localization through chemoattractant signaling; it is a genuine but non-core, context-specific role. Supporting Evidence: PMID:40934557 This localization required GPCR Car1/3 and G-protein signaling |
| GO:0005096 GTPase activator activity | IDA PMID:21103944 Chemoattractant-mediated Rap1 activation requires GPCR/G pro... | MARK AS OVER ANNOTATED | Summary: This paper shows that rapid Rap1 activation upon cAMP stimulation is absent in cells lacking cAR1/cAR3 or Galpha2, placing the receptor upstream of Rap1 GTPase activation. However, GTPase activator activity (GO:0005096, GAP activity) is a molecular function the receptor does not itself possess, because cAR3 is an upstream GPCR and Rap1 activation (GTP loading) is mediated by downstream exchange factors, not by a GAP. Reason: The receptor is required for chemoattractant-induced Rap1 activation but does not have intrinsic GTPase activator (GAP) activity; the effect is indirect, transduced through G proteins and downstream regulators. The molecular-function assignment over-attributes an effector activity to the upstream receptor. Its role is better captured as involvement in the GPCR signaling pathway. Supporting Evidence: PMID:21103944 The rapid Rap1 activation upon cAMP chemoattractant stimulation was absent in cells lacking chemoattractant cAMP receptors cAR1/cAR3 or a subunit of the heterotrimeric G-protein complex GΞ±2 |
| GO:0006935 chemotaxis | IGI PMID:9578623 Switching of chemoattractant receptors programs development ... | ACCEPT | Summary: cAR3, redundantly with cAR1, mediates chemotaxis toward cAMP; constitutively expressed cAR3 confers chemotactic responses and rescues the car1-/car3- defect. This is a core biological process for the receptor. Reason: Directly assessed capacity of cAR3 to mediate chemotaxis, with genetic interaction to cAR1 (car1-/car3- double mutant). Chemotaxis toward cAMP is a central output of cAR3 signaling. Supporting Evidence: PMID:9578623 assessed the capacity of each to mediate chemotaxis |
| GO:0010856 adenylate cyclase activator activity | IMP PMID:9578623 Switching of chemoattractant receptors programs development ... | MARK AS OVER ANNOTATED | Summary: cAR3 mediates activation of adenylyl cyclase (cAMP relay), lost in car1-/car3- cells. However, as a GPCR it activates adenylyl cyclase indirectly through heterotrimeric G proteins rather than binding and activating the cyclase directly, so adenylate cyclase activator activity as a molecular function of the receptor over-attributes an effector activity. Reason: The receptor's requirement for adenylyl cyclase activation is real, but the activation is G-protein-mediated and indirect. The role is better captured by the pathway term adenylate cyclase-activating GPCR cAMP receptor signaling pathway (GO:0140582 and GO:0007189) than by a direct cyclase-activator molecular function assigned to the receptor. Supporting Evidence: PMID:9578623 activation of adenylyl cyclase |
| GO:0031152 aggregation involved in sorocarp development | IGI PMID:9578623 Switching of chemoattractant receptors programs development ... | ACCEPT | Summary: cAR3, together with cAR1, drives the aggregation of individual amoebae into a multicellular organism; constitutively expressed receptors mediate aggregation-stage responses and rescue the car1-/car3- developmental defect. This is a core developmental role. Reason: The receptors mediate identical responses during the aggregation stage and rescue the developmental defect of car1-/car3- cells, directly linking cAR3 to aggregation in the developmental (sorocarp) program. Supporting Evidence: PMID:9578623 rescue the developmental defect of car1-/car3- cells PMID:9578623 mediate identical responses during the aggregation stage of development |
| GO:0140582 adenylate cyclase-activating G protein-coupled cAMP receptor signaling pathway | IGI PMID:7949426 Two cAMP receptors activate common signaling pathways in Dic... | ACCEPT | Summary: cAR1 and cAR3 activate common signaling pathways, including cAMP relay (adenylyl cyclase activation), by coupling to the same heterotrimeric G protein. This cAMP-ligand-specific, adenylate cyclase-activating pathway term is the most precise process annotation for cAR3. Reason: Genetic evidence (car1- and car1-/car3- phenotypes) shows cAR3 mediates cAMP relay through a shared G protein, precisely matching this pathway term. Supporting Evidence: PMID:7949426 We conclude that the functions of the cAR1 and cAR3 receptors are partially redundant and that both interact with the same heterotrimeric G-protein to mediate these and other responses |
| GO:0005886 plasma membrane | TAS PMID:15473840 Chemoattractant signaling in dictyostelium discoideum. | ACCEPT | Summary: Plasma-membrane localization asserted in an authoritative review of chemoattractant signaling, consistent with cAR3 being a cell-surface 7TM receptor. Reason: cAR3 is a cell-surface cAMP receptor located in the plasma membrane, the site of chemoattractant detection. Supporting Evidence: PMID:2722797 four forms of the cell surface receptor |
| GO:0030552 cAMP binding | IDA PMID:2722797 The cyclic nucleotide specificity of eight cAMP-binding prot... | ACCEPT | Summary: Direct ligand-specificity analysis of the Dictyostelium cell-surface cAMP receptors (including cAR3) demonstrating cAMP binding. cAMP binding is a core molecular activity of the receptor. Reason: cAR3 is one of the four cell-surface cAMP receptors whose cyclic nucleotide binding specificity was directly characterized; cAMP binding is intrinsic to its receptor function. Supporting Evidence: PMID:2722797 four forms of the cell surface receptor |
| GO:0030552 cAMP binding | IDA PMID:1537842 The cyclic nucleotide specificity of three cAMP receptors in... | ACCEPT | Summary: Direct [3H]cAMP binding assays established cAR3 affinity states (approximately 20 and 500 nM), confirming intermediate-affinity cAMP binding. Core molecular activity. Reason: Radioligand binding measurements directly demonstrate cAMP binding by cAR3 with defined affinity states, a central feature of the receptor. Supporting Evidence: PMID:1537842 20 and 500 nM for cAR3 |
| GO:0005515 protein binding | IPI PMID:16781008 The COP9 signalosome regulates cell proliferation of Dictyos... | KEEP AS NON CORE | Summary: A yeast two-hybrid screen identified the COP9 signalosome subunit CSN5 as a potential interacting partner of a Dictyostelium cell-surface receptor. This bare protein binding term is uninformative about molecular function and the interaction is described as potential. Reason: Per curation guidance, bare protein binding is not retained as a core function. The reported CSN5 interaction is a specific but preliminary (yeast two-hybrid, potential) finding whose functional significance for cAR3 is unestablished; it is kept as non-core rather than treated as a core molecular function. Supporting Evidence: PMID:16781008 we have identified the CSN5 subunit as a potential interacting partner of a cell surface receptor of Dictyostelium |
| GO:0001646 cAMP receptor activity | IDA PMID:9578623 Switching of chemoattractant receptors programs development ... | ACCEPT | Summary: Direct evidence that cAR3 functions as a cAMP receptor, since constitutive expression confers cAMP-sensing responses. This is the defining core molecular function of the gene product. Reason: cAR3 directly binds cAMP and transduces the signal as a receptor, as demonstrated by reconstitution of cAMP responses upon its expression. This is the core molecular function. Supporting Evidence: PMID:9578623 assessed the capacity of each to mediate chemotaxis |
| GO:0001646 cAMP receptor activity | IGI PMID:9578623 Switching of chemoattractant receptors programs development ... | ACCEPT | Summary: Genetic-interaction evidence (with cAR1) supporting cAR3 cAMP receptor activity; the two receptors are partially redundant in cAMP sensing. Core molecular function. Reason: The car1-/car3- double mutant loses cAMP responsiveness while single mutants retain it, genetically confirming cAR3 acts as a cAMP receptor redundantly with cAR1. Supporting Evidence: PMID:9578623 rescue the developmental defect of car1-/car3- cells |
| GO:0030552 cAMP binding | IMP PMID:9578623 Switching of chemoattractant receptors programs development ... | ACCEPT | Summary: Mutational/expression analysis supporting cAMP binding by cAR3 as part of its receptor function. Core molecular activity, concordant with the direct binding studies. Reason: cAMP binding is intrinsic to cAR3 receptor activity and is supported across binding assays and functional expression studies. Supporting Evidence: PMID:1537842 20 and 500 nM for cAR3 |
Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)