carB

id: P34907
gene_symbol: carB
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:44689
  label: Dictyostelium discoideum
description: Cyclic AMP receptor 2 (cAR2/carB) is one of four serpentine
  (seven-transmembrane) G protein-coupled receptors for extracellular cAMP in the
  social amoeba Dictyostelium discoideum. It is a lower-affinity cAMP receptor that
  is expressed later than cAR1, appearing only after cells have aggregated and then
  preferentially in prestalk cells at the mound-to-slug stage. Signaling through
  heterotrimeric G proteins, cAR2 couples extracellular cAMP to downstream responses
  including adenylyl cyclase activation and developmentally regulated gene
  expression. It is required for cAMP-directed sorting/patterning of prestalk cells,
  for normal tip formation, and for progression through late multicellular
  development; cells lacking cAR2 arrest at the tight-mound stage and over-express
  prespore markers. cAR2 belongs to the Dictyostelium cAR family (cAR1-cAR4), whose
  members are deployed sequentially during development and differ in cAMP affinity
  and C-terminal sequence.
existing_annotations:
- term:
    id: GO:0004930
    label: G protein-coupled receptor activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: cAR2 is a bona fide seven-transmembrane G protein-coupled receptor for
      cAMP whose responses are mediated by heterotrimeric G proteins. This is a core
      molecular function and the phylogenetic inference is well supported by direct
      characterization of the Dictyostelium cAR family.
    action: ACCEPT
    reason: cAR2 belongs to the cAMP receptor GPCR family, has seven predicted
      transmembrane helices, and signals via G proteins, consistent with GPCR
      activity as a core function.
    supported_by:
    - reference_id: PMID:8436297
      supporting_text: The receptors for cAMP are members of the family of
        cell-surface receptors that are linked to G proteins and characterized by
        seven putative transmembrane domains.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: As a cell-surface cAMP receptor with seven transmembrane domains, cAR2
      is active in the plasma membrane. This is a core localization for the receptor.
    action: ACCEPT
    reason: cAR2 is a multi-pass cell-surface receptor; plasma membrane is where it
      binds extracellular cAMP and transduces signal.
    supported_by:
    - reference_id: PMID:8436297
      supporting_text: The receptors for cAMP are members of the family of
        cell-surface receptors that are linked to G proteins and characterized by
        seven putative transmembrane domains.
- term:
    id: GO:0007189
    label: adenylate cyclase-activating G protein-coupled receptor signaling pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: When expressed, cAR2 can mediate activation of adenylyl cyclase, so
      participation in an adenylate cyclase-activating GPCR signaling pathway is
      supported experimentally and by phylogenetic inference from the cAR family.
    action: ACCEPT
    reason: cAR2 couples cAMP binding to adenylyl cyclase activation via G proteins,
      as directly shown for the receptor subtype.
    supported_by:
    - reference_id: PMID:9578623
      supporting_text: assessed the capacity of each to mediate chemotaxis,
        activation of adenylyl cyclase and actin polymerization
- term:
    id: GO:0004888
    label: transmembrane signaling receptor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: This is a correct but non-specific parent of G protein-coupled receptor
      activity. A more informative, already-curated child term (GO:0004930) captures
      the same function more precisely.
    action: MODIFY
    reason: The general transmembrane signaling receptor activity term is subsumed by
      the more specific GPCR activity that is separately annotated; replace with the
      specific term.
    proposed_replacement_terms:
    - id: GO:0004930
      label: G protein-coupled receptor activity
    supported_by:
    - reference_id: PMID:8436297
      supporting_text: The receptors for cAMP are members of the family of
        cell-surface receptors that are linked to G proteins and characterized by
        seven putative transmembrane domains.
- term:
    id: GO:0004930
    label: G protein-coupled receptor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro-based electronic annotation of GPCR activity from the cAMP
      receptor domain signature. This agrees with the IBA and experimental evidence
      and is a core molecular function.
    action: ACCEPT
    reason: cAR2 is a member of the Dictyostelium cAMP receptor GPCR family; GPCR
      activity is correct and core.
    supported_by:
    - reference_id: PMID:8436297
      supporting_text: The receptors for cAMP are members of the family of
        cell-surface receptors that are linked to G proteins and characterized by
        seven putative transmembrane domains.
- term:
    id: GO:0007165
    label: signal transduction
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: Correct but very general. cAR2 does participate in signal transduction,
      but a more specific GPCR signaling pathway term better captures its role.
    action: KEEP_AS_NON_CORE
    reason: Signal transduction is a high-level parent of the specific GPCR signaling
      pathway annotations; retain as non-core context.
    supported_by:
    - reference_id: PMID:8436297
      supporting_text: The receptors for cAMP are members of the family of
        cell-surface receptors that are linked to G proteins and characterized by
        seven putative transmembrane domains.
- term:
    id: GO:0007166
    label: cell surface receptor signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: Correct but a general parent of G protein-coupled receptor signaling
      pathway, which is the more precise annotation for cAR2.
    action: KEEP_AS_NON_CORE
    reason: cAR2 is a cell-surface receptor, but the more specific GPCR signaling
      pathway term is preferred; retain this as non-core.
    supported_by:
    - reference_id: PMID:8436297
      supporting_text: The receptors for cAMP are members of the family of
        cell-surface receptors that are linked to G proteins and characterized by
        seven putative transmembrane domains.
- term:
    id: GO:0007186
    label: G protein-coupled receptor signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: cAR2 transduces extracellular cAMP through a G protein-coupled receptor
      signaling pathway. This is a core biological process for the receptor.
    action: ACCEPT
    reason: cAR2 signaling is mediated by G proteins, placing it squarely in the GPCR
      signaling pathway.
    supported_by:
    - reference_id: PMID:8436297
      supporting_text: The receptors for cAMP are members of the family of
        cell-surface receptors that are linked to G proteins and characterized by
        seven putative transmembrane domains.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Correct but non-specific. cAR2 is a plasma membrane cell-surface
      receptor; the more specific plasma membrane term is preferred.
    action: MODIFY
    reason: Generic membrane localization should be replaced by the specific plasma
      membrane term appropriate for a cell-surface receptor.
    proposed_replacement_terms:
    - id: GO:0005886
      label: plasma membrane
    supported_by:
    - reference_id: PMID:8436297
      supporting_text: The receptors for cAMP are members of the family of
        cell-surface receptors that are linked to G proteins and characterized by
        seven putative transmembrane domains.
- term:
    id: GO:0030552
    label: cAMP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: cAR2 binds cAMP as its ligand. This InterPro-based electronic annotation
      is consistent with direct binding measurements and is a core molecular
      function.
    action: ACCEPT
    reason: Direct [3H]cAMP binding to cAR2 has been demonstrated; cAMP binding is the
      defining ligand-recognition activity of the receptor.
    supported_by:
    - reference_id: PMID:1537842
      supporting_text: We have expressed three receptor subtypes, cAR1, cAR2, and
        cAR3, in growing cells and have investigated their affinity and
        pharmacological specificity in a series of [3H]cAMP binding studies.
- term:
    id: GO:0035589
    label: G protein-coupled purinergic nucleotide receptor signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: involved_in
  review:
    summary: This term was assigned by an automated inter-ontology logical inference
      from cAMP receptor activity. The Dictyostelium cAR receptors are cyclic-AMP
      chemoattractant receptors, not purinergic (ATP/ADP/adenosine) nucleotide
      receptors in the sense captured by this term. The mapping mischaracterizes the
      receptor's signaling pathway.
    action: REMOVE
    reason: This is an over-propagated electronic inference. cAR2 responds to the
      diffusible second messenger cAMP as a developmental chemoattractant; it is not a
      purinergic nucleotide receptor. The GPCR signaling pathway term already captures
      its role correctly without the misleading purinergic classification.
    supported_by:
    - reference_id: PMID:2722797
      supporting_text: the cell surface receptors participate in the transduction of
        the cAMP signal during chemotaxis and cell differentiation
- term:
    id: GO:0009642
    label: response to light intensity
  evidence_type: HEP
  original_reference_id: PMID:41057014
  qualifier: acts_upstream_of_or_within
  review:
    summary: A high-throughput expression annotation. carB transcript is
      down-regulated under dark relative to light in a transcriptomic study of the
      light-mediated unicellular-to-multicellular transition. This reflects
      transcriptional responsiveness rather than a core molecular function of the
      receptor.
    action: KEEP_AS_NON_CORE
    reason: The evidence is expression-level (HEP), showing carB is among genes
      down-regulated in the dark; it is a peripheral developmental/environmental
      response, not a core function.
    supported_by:
    - reference_id: PMID:41057014
      supporting_text: some downregulated genes including adenylate cyclase (acrA) and
        cyclic AMP receptor (CarB) could reduce the cell aggregation during dark
        incubation
- term:
    id: GO:0010854
    label: adenylate cyclase regulator activity
  evidence_type: IMP
  original_reference_id: PMID:9578623
  qualifier: enables
  review:
    summary: Functional expression experiments showed cAR2 can mediate activation of
      adenylyl cyclase, consistent with the receptor acting as an upstream regulator
      of adenylyl cyclase through its G protein coupling. Supported by experimental
      (IMP) evidence.
    action: ACCEPT
    reason: cAR2 was directly shown to mediate adenylyl cyclase activation when
      expressed, supporting an adenylate cyclase regulator activity as part of its
      signaling output.
    supported_by:
    - reference_id: PMID:9578623
      supporting_text: assessed the capacity of each to mediate chemotaxis,
        activation of adenylyl cyclase and actin polymerization
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: PMID:15473840
  qualifier: located_in
  review:
    summary: cAR2 is a cell-surface cAMP receptor located in the plasma membrane. This
      is a core localization and is consistent with its multi-pass membrane
      architecture.
    action: ACCEPT
    reason: As a seven-transmembrane cell-surface receptor, cAR2 resides in the plasma
      membrane where it binds extracellular cAMP.
    supported_by:
    - reference_id: PMID:8436297
      supporting_text: The receptors for cAMP are members of the family of
        cell-surface receptors that are linked to G proteins and characterized by
        seven putative transmembrane domains.
- term:
    id: GO:0007165
    label: signal transduction
  evidence_type: TAS
  original_reference_id: PMID:15473840
  qualifier: acts_upstream_of_or_within
  review:
    summary: Correct but very general. cAR2 participates in signal transduction, more
      precisely as a GPCR signaling pathway component.
    action: KEEP_AS_NON_CORE
    reason: High-level parent term; retained as non-core context alongside the
      specific GPCR signaling pathway annotation.
    supported_by:
    - reference_id: PMID:2722797
      supporting_text: the cell surface receptors participate in the transduction of
        the cAMP signal during chemotaxis and cell differentiation
- term:
    id: GO:0030552
    label: cAMP binding
  evidence_type: IDA
  original_reference_id: PMID:2722797
  qualifier: enables
  review:
    summary: Direct biochemical analysis of Dictyostelium cell-surface cAMP receptors
      (including cAR2) demonstrated cAMP binding and characterized their nucleotide
      specificity. cAMP binding is the defining ligand-recognition activity of cAR2.
    action: ACCEPT
    reason: Experimental (IDA) evidence for cAMP binding by the cell-surface receptor
      family; this is a core molecular function.
    supported_by:
    - reference_id: PMID:2722797
      supporting_text: 'Eight forms of cAMP-binding proteins have been described in
        this organism: four forms of a cell surface receptor'
- term:
    id: GO:0010628
    label: positive regulation of gene expression
  evidence_type: IEP
  original_reference_id: PMID:8436297
  qualifier: acts_upstream_of_or_within
  review:
    summary: cAR2 signaling influences the developmental gene-expression program.
      Loss of cAR2 alters cell-type gene expression (over-expression of prespore
      markers), indicating cAR2 acts upstream of developmental gene regulation. This
      is a downstream developmental consequence rather than a core molecular function.
    action: KEEP_AS_NON_CORE
    reason: The receptor regulates expression of developmentally regulated genes as a
      downstream effect of signaling; retain as non-core developmental context.
    supported_by:
    - reference_id: PMID:8436297
      supporting_text: they exhibit an enhanced expression of prespore-specific mRNA
- term:
    id: GO:0010629
    label: negative regulation of gene expression
  evidence_type: IEP
  original_reference_id: PMID:8436297
  qualifier: acts_upstream_of_or_within
  review:
    summary: In wild-type aggregates cAR2 normally restrains prespore-specific gene
      expression; the enhanced prespore mRNA in cAR2-null cells indicates cAR2 acts
      upstream of negative regulation of these genes. A downstream developmental
      effect, not a core molecular function.
    action: KEEP_AS_NON_CORE
    reason: Derepression of prespore markers in the mutant implies cAR2 normally
      contributes to negative regulation of that gene set; retain as non-core.
    supported_by:
    - reference_id: PMID:8436297
      supporting_text: they exhibit an enhanced expression of prespore-specific mRNA
- term:
    id: GO:0030552
    label: cAMP binding
  evidence_type: IDA
  original_reference_id: PMID:1537842
  qualifier: enables
  review:
    summary: Direct [3H]cAMP binding studies of expressed cAR2 demonstrated cAMP
      binding, with cAR2 showing much lower/less-detectable affinity than cAR1 in
      physiological buffer (measurable only in ammonium sulfate). cAMP binding is a
      core molecular function.
    action: ACCEPT
    reason: Experimental (IDA) demonstration of cAMP binding by cAR2; the low
      apparent affinity distinguishes it from cAR1 but binding is genuine and core.
    supported_by:
    - reference_id: PMID:1537842
      supporting_text: there was one affinity state of 4 nM for cAR1 and 11 nM for
        cAR2
- term:
    id: GO:0031154
    label: culmination involved in sorocarp development
  evidence_type: IMP
  original_reference_id: PMID:8436297
  qualifier: acts_upstream_of_or_within
  review:
    summary: cAR2-null cells arrest at the tight-mound stage and fail normal tip
      formation and late development, so cAR2 is required for progression toward
      culmination and fruiting-body (sorocarp) formation. This is a multicellular
      developmental role rather than a core molecular function.
    action: KEEP_AS_NON_CORE
    reason: Loss-of-function experimental evidence links cAR2 to late multicellular
      morphogenesis/culmination; retained as a non-core developmental process.
    supported_by:
    - reference_id: PMID:8436297
      supporting_text: detained at the tight mound stage
- term:
    id: GO:0001646
    label: cAMP receptor activity
  evidence_type: TAS
  original_reference_id: PMID:15473840
  qualifier: enables
  review:
    summary: cAMP receptor activity is the most precise molecular-function
      description of cAR2 as a cell-surface receptor that binds extracellular cAMP and
      transduces the signal via G proteins. This is the primary core function.
    action: ACCEPT
    reason: cAR2 is a defining member of the Dictyostelium cAMP receptor family; cAMP
      receptor activity is the correct, specific core molecular function.
    supported_by:
    - reference_id: PMID:2722797
      supporting_text: the cell surface receptors participate in the transduction of
        the cAMP signal during chemotaxis and cell differentiation
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000108
  title: Automatic assignment of GO terms using logical inference, based on on inter-ontology
    links
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:1537842
  title: The cyclic nucleotide specificity of three cAMP receptors in Dictyostelium.
  findings:
  - statement: cAR2 was expressed and assayed by [3H]cAMP binding; unlike cAR1 and
      cAR3 it showed no detectable affinity in phosphate buffer and only an 11 nM
      affinity state in ammonium sulfate, marking cAR2 as a comparatively
      low/atypical-affinity cAMP receptor.
    supporting_text: In phosphate buffer, there were two affinity states of about 30
      and 300 nM for cAR1 and 20 and 500 nM for cAR3 but no detectable affinity for
      cAR2.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified J Biol Chem 1992 paper; directly measures cAR2 cAMP
      binding affinity and specificity, supporting the cAMP binding molecular
      function.
- id: PMID:15473840
  title: Chemoattractant signaling in dictyostelium discoideum.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Review of Dictyostelium chemoattractant (cAMP receptor) signaling;
      abstract-only in cache, cited for the well-established plasma-membrane
      localization, cAMP receptor activity and signal transduction annotations.
- id: PMID:2722797
  title: The cyclic nucleotide specificity of eight cAMP-binding proteins in Dictyostelium
    discoideum is correlated into three groups.
  findings:
  - statement: The four cell-surface cAMP receptors (including cAR2) form one
      pharmacological group and bind cAMP to transduce the signal during chemotaxis
      and cell differentiation.
    supporting_text: the cell surface receptors participate in the transduction of the
      cAMP signal during chemotaxis and cell differentiation
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified J Biol Chem 1989 paper; characterizes cAMP binding
      and specificity of the cell-surface receptor group that includes cAR2.
- id: PMID:41057014
  title: Transcriptomic and metabolomic insights into light-mediated unicellular-to-multicellular
    transition in Dictyostelium discoideum.
  findings:
  - statement: carB (CarB) is among genes down-regulated under dark relative to light
      during the unicellular-to-multicellular transition, linking cAR2 expression to
      light-modulated development.
    supporting_text: some downregulated genes including adenylate cyclase (acrA) and
      cyclic AMP receptor (CarB) could reduce the cell aggregation during dark
      incubation
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Full-text available; supports the HEP response-to-light-intensity
      annotation via transcriptomic down-regulation of carB in the dark.
- id: PMID:8436297
  title: CAR2, a prestalk cAMP receptor required for normal tip formation and late
    development of Dictyostelium discoideum.
  findings:
  - statement: cAR2 is a G protein-linked, seven-transmembrane cell-surface receptor
      for cAMP.
    supporting_text: The receptors for cAMP are members of the family of cell-surface
      receptors that are linked to G proteins and characterized by seven putative
      transmembrane domains.
  - statement: cAR2 is expressed only after aggregation and preferentially in prestalk
      cells.
    supporting_text: CAR2 is expressed only after cells have aggregated and, then,
      preferentially in prestalk cells.
  - statement: cAR2-null cells arrest at the tight-mound stage and over-express
      prespore markers, and cAR2 is required for cAMP-directed prestalk sorting.
    supporting_text: CAR2 may be required for cAMP-directed sorting of prestalk cells
      during pattern formation within the aggregation mound.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified Genes Dev 1993 primary paper defining cAR2; the
      knockout phenotype and prestalk expression underpin the developmental
      annotations. Abstract-only in cache but title and abstract directly support the
      cited claims.
- id: PMID:9578623
  title: 'Switching of chemoattractant receptors programs development and morphogenesis
    in Dictyostelium: receptor subtypes activate common responses at different agonist
    concentrations.'
  findings:
  - statement: cAR2, when expressed, can mediate chemotaxis, adenylyl cyclase
      activation and actin polymerization, and cAR subtypes activate common responses
      at different cAMP concentrations.
    supporting_text: assessed the capacity of each to mediate chemotaxis, activation
      of adenylyl cyclase and actin polymerization
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified Dev Biol 1998 paper; provides the IMP evidence that
      cAR2 can activate adenylyl cyclase, supporting the adenylate cyclase regulator
      activity annotation.
core_functions:
- description: cAR2 is a cell-surface, seven-transmembrane G protein-coupled receptor
    that binds extracellular cAMP and transduces the signal through heterotrimeric G
    proteins at the plasma membrane. It is a comparatively low/atypical-affinity
    member of the cAR family expressed after aggregation in prestalk cells.
  molecular_function:
    id: GO:0001646
    label: cAMP receptor activity
  locations:
  - id: GO:0005886
    label: plasma membrane
  directly_involved_in:
  - id: GO:0007186
    label: G protein-coupled receptor signaling pathway
  supported_by:
  - reference_id: PMID:8436297
    supporting_text: The receptors for cAMP are members of the family of cell-surface
      receptors that are linked to G proteins and characterized by seven putative
      transmembrane domains.
  - reference_id: PMID:2722797
    supporting_text: the cell surface receptors participate in the transduction of the
      cAMP signal during chemotaxis and cell differentiation
- description: Through its G protein coupling, cAR2 acts upstream as a regulator of
    adenylyl cyclase, mediating cAMP-triggered adenylyl cyclase activation as part of
    the developmental signaling relay.
  molecular_function:
    id: GO:0010854
    label: adenylate cyclase regulator activity
  directly_involved_in:
  - id: GO:0007189
    label: adenylate cyclase-activating G protein-coupled receptor signaling pathway
  supported_by:
  - reference_id: PMID:9578623
    supporting_text: assessed the capacity of each to mediate chemotaxis, activation
      of adenylyl cyclase and actin polymerization