RECEPTORS

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RECEPTORS AND HAS_PART : STARTED

There is a proposal to change the binding relationships, and kinase activities of the receptors to HAS_PART relationships.

  • Currently the receptors are linked to the ligand-binding GO term via an is_a relationship. This is incorrect. For example, epidermal growth factor receptor activity ; GO:0005006' is described as 'combining with EGF to initiate a change in cell activity'. The kinase activity of the receptor is separate to the EGF-binding activity and thus creates TPV having the receptor as is_a kinase activity.
  • The problem is that a receptor molecule has multiple 'activities' (bind the ligand and passing the signal on). Therefore the option of moving receptors to the process ontology was discussed at length but was decided against.
  • We need to separate the name of a gene product (EGFR) with the activities of the gene product.

For an overview of how the HAS_PART receptor proposal, see slide 35 of the following presentation from the LA GOC meeting, May 2011.


Related receptor SF item:


  • Started (Aug 16th 2011, revision 1.2184) adding in HAS_PART relationships for the growth factor receptors, and Wnt receptor.
  • Continued to add them in for receptors where there is already an 'x binding' term. Apart from the VEGFR, I haven't made new binding terms, while the protein binding mode is being cleaned-up.

TRANSMEMBRANE RECEPTORS : DONE

There was a proposal (January 2011) to clean up the transmembrane receptor terms. The proposal was 2 fold:

  • 1. Remove the cellular component (transmembrane) information from the term name.
  • 2. Update the definitions of terms to show it’s a receptor that possesses kinase activity, and NOT phosphorylation of a receptor.

After describing the proposal via an annotation call on January 10th 2011, it was decided that:

  • The membrane localization of the receptor was integral to its activity (transmitting a signal from one side of the membrane to the other). Therefore the 'transmembrane' information should stay in the term name, but the definitions should be updated to make this clearer.

UPDATE FROM MAY 2011:

  • The definitions of the TM receptor terms have been updated to show that it is a receptor that possesses kinase activity (for example), and transmits a signal across a membrane.


SIGNALING RECEPTORS VS CARGO RECEPTORS : DONE

BACKGROUND

  • Many receptors don't signal but instead internalize their ligand by receptor-mediated endocytosis. The old structure of GO did not account for this and all receptor terms were under 'signal transducer activity'. Initially there was discussion about whether endocytic receptors signal when they respond to their ligand to internalize. However, it was decided that in GO, it would be simplest to use signaling receptor to describe receptors that are coupled to a signal transduction cascade.
  • It's complicated by the fact that some signaling receptors (eg EGFR) internalize with their ligand. For these, I created 'rregulation of signal transduction by receptor internalization ; GO:0038009' process terms, along with 'endosomal signal transduction ; GO:2000803'.
  • The options were discussed at the signaling call on July 18th 2011. Based on the existing mappings for 'receptor activity', it was decided to move 'receptor activity' to be directly under 'molecular function' and create new terms for 'signaling receptors' and 'cargo/endocytic receptors' (OPTION 1 in the discussion discussion section). These edits were added to the ontology on AUGUST 2nd 2011 (revision 2.2140).
  • PLEASE COULD THE SIGNALING WG CHECK TO SEE IF ANY RECEPTOR TERMS LOOK IN THE WRONG PLACE !!


Some Notes/Outstanding Questions:

  • PATTERN RECOGNITION RECEPTORS: I haven't assigned pattern recognition receptors to cargo or signaling because they can be split into those that internalize their ligand without transducing a signal, and those that act via a signal transduction pathway (see http://en.wikipedia.org/wiki/Pattern_recognition_receptor).

However, given GO:0002221

pattern recognition receptor signaling pathway ; GO:0002221
--[partof]pattern recognition receptor activity ; GO:0008329
    • Q1: Do we want a term 'signaling pattern recognition receptor activity ; GO:NEW'? to be under GO:0002221 instead?
    • Q2: Are any of the current children of GO:0008329 signaling receptors?


  • LIPOPROTEIN PARTICLE RECEPTORS. I moved the lipoprotein particle receptor terms to be cargo receptors. Although members of the LDLR family are involved in signal transduction, they appear to do this by binding non-LDL ligands (eg reelin, PDGF etc). I've made a term 'reelin receptor activity ; GO:0038025' to cover the former. For the LRP1 protein that may transduce a signal by being proteolytically cleaved and the intracellular domain translocating to the nucleus, it's not clear what ligand is being bound, so 'signaling receptor activity ; GO:0038023' would be the most accurate term for annotation.


  • APOLIPOPROTEIN RECEPTORS. Not sure about apolipoprotein receptor activity ; GO:0030226. It's child 'apolipoprotein A-I receptor activity ; GO:0034188' has been used to annotate a clear signaling receptor. I've given GO:0034188 a signaling receptor parent, but kept GO:0030226 directly under receptor activity for now.
    • Q: Do we need to create 'apolipoprotein cargo receptor' and 'apolipoprotein signaling receptor' terms.


X-ACTIVATED RECEPTORS : STARTED

  • At the February 2011 signaling workshop, it was agreed that, to distinguish the activity of the receptor from the gene product name, we should change receptors to 'x-activated receptor activity'. This fits in with the HAS_PART proposal, since 'epidermal growth factor-activated receptor activity' would HAS_PART 'epidermal growth factor binding'.
  E.g:
  epidermal growth factor receptor activity TO epidermal growth factor-activated receptor activity
  Wnt receptor activity TO Wnt-activated receptor activity
  activin receptor activity TO activin-activated receptor activity


  • : STARTED Started (Aug 16th 2011, revision 1.2184) changing the TM growth factor receptors to X-activated receptor activity.



LIGAND-GATED ION CHANNELS

Q: Are ligand-gated ion channels, receptors, and if so should they be in the receptor node?

At the moment (June 2011), ligand-gated ion channels are separate from 'receptor activity'. There are ligand-gated ion channel terms with 'receptor' synonyms:

ligand-gated ion channel activity ; GO:0015276 (synonym [NARROW] :ionotropic neurotransmitter receptor extracellular ATP-gated cation channel activity ; GO:0004931 (synonym [RELATED]: P2X receptor) inositol 1,4,5-trisphosphate-sensitive calcium-release channel activity ; GO:0005220 (see below)


IP3 RECEPTOR

There was discussion (June 2011) within the signaling WG about whether 'inositol-1,4,5-trisphosphate receptor activity ; GO:0008095' and 'inositol 1,4,5-trisphosphate-sensitive calcium-release channel activity ; GO:0005220' are synonymous. It was agreed they are, so the terms were merged by Becky (June 2011).


IONOTROPIC RECEPTORS

Are 'ionotropic receptors' just ligand-gated ion channels? If so, there is redundancy between:

  glutamate-gated calcium ion channel activity ; GO:0022849
  &
  ionotropic glutamate receptor activity ; GO:0004970

For a background, see http://www.sinauer.com/neuroscience4e/animations5.3.html.


GPCRs

The nomenclature of the GPCRs need to be standardized.

See SF item from Florence: http://sourceforge.net/tracker/?func=detail&aid=3423752&group_id=36855&atid=440764 : DONE ==

There is also some pharmacological information in some of the GPCR receptor terms, which needs looking at. I've removed the 'muscarinic/nicotinic' nomenclature, but there's others that can probably be merged into their parents.



DODGY RECEPTOR TERMS

  • The following receptor terms need looking at (Oct 2011). They contain information about pharmacological properties, cell-type, affinity etc.
  • Need to decide whether to keep-and-better-define, merge into parents or obsolete.
dopamine D1 receptor activity ;GO:0001589
dopamine D2 receptor activity ;GO:0001589
dopamine D3 receptor activity ;GO:0001589
dopamine D4 receptor activity ;GO:0001589
dopamine D5 receptor activity ;GO:0001589
A G-protein coupled receptor that binds dopamine and has the pharmacological characteristics of classic D5 receptors.

DONE: Merged into parent terms, and keep D1-D5 as narrow synonyms:

  • dopamine receptor activity, coupled via Gi/Go ; GO:0001591 (D2, D3, D4)
  • dopamine receptor activity, coupled via Gs ; GO:0001588 (D1, D5)
  • NB: InterPro domains from 'dopamine receptor activity ; GO:0004952' may be better mapped to GO:0001591 or GO:0001588. Submit SF item once I've merged the D1-D5 terms
endothelin-A receptor activity ; GO:0001599
A G-protein coupled receptor that preferentially binds endothelin 1.
endothelin-B receptor activity ; GO:0001600
A G-protein coupled receptor that binds all endothelin molecules with approximately equal affinity.

DONE:

  • Merged into parent: endothelin receptor activity ; GO:0004962'.
alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate selective glutamate receptor activity ; GO:0004971
An ionotropic glutamate receptor activity that exhibits fast gating by glutamate and acts by opening a cation channel permeable to sodium, potassium, and, in the absence of a GluR2 subunit, calcium.
kainate selective glutamate receptor activity ; GO:0015277
An ionotropic glutamate receptor activity that exhibits fast gating by glutamate, acts by opening a cation channel permeable to sodium and potassium, and for which kainate is an agonist.
N-methyl-D-aspartate selective glutamate receptor activity ; GO:0004972
An ionotropic glutamate receptor activity that exhibits slow gating by glutamate, acts by opening a nonselective cation channel, and can  be activated by L-aspartate.

TODO:

  • Merge into parent: ionotropic glutamate receptor activity ; GO:0004970'?
  • NB: The receptor is named based on its ability to also be activated by the artificial glutamate analog AMPA. [2]. There are 3 types of families (AMPA, Kainate and NMDA).
  • Could create terms: kainate receptor activity ; GO etc....
  • NB: ionotropic glutamate receptors are ligand-gated ion channels. Therefore need to connect GO:0004970 with the channel-node.
angiotensin type I receptor activity ; GO:0001596
An angiotensin receptor activity that acts via Gq-mediated activation of phospholipase C followed by phosphoinositide hydrolysis and Ca2+ signaling, and may act via additional signaling mechanisms.
(change to 'receptor activity, coupled via G…. ?)
angiotensin type II receptor activity ; GO:0004945
An angiotensin receptor activity that acts via Gi protein coupling and cGMP (NO) generation, and may also act via additional signaling  mechanisms.
group II metabotropic glutamate receptor activity ; GO:0001641
A G-protein coupled receptor that is activated by trans-1-aminocyclopentane-1,3-dicarboxylic acid (t-ACPD) and inhibits adenylate cyclase activity.
group III metabotropic glutamate receptor activity ; GO:0001642
A G-protein coupled receptor that is activated by L-AP-4 and inhibits adenylate cyclase activity.
high affinity IgA receptor activity ; GO:0002170
high affinity IgE receptor activity ; GO:0019768
high affinity IgG receptor activity ; GO:0019771
high affinity IgM receptor activity ; GO:0002172
low affinity IgA receptor activity ; GO:0002171
low affinity IgE receptor activity ; GO:0019769
low affinity IgG receptor activity ; GO:0019772
low affinity IgM receptor activity ; GO:0002173
Example def: Combining with high affinity with an immunoglobulin of an IgA isotype via the Fc region to initiate a change in cell activity.

TODO: There are many high/low affinity transport and transporter terms in GO. Leave these for the moment.


lysosphingolipid and lysophosphatidic acid receptor activity ; GO:0001619
Combining with lysosphingolipid or lysophosphatidic acid to initiate a change in cell activity.

TODO:

  • OBSOLETE (Nov 14th 2011). Reason: This term represents two separate activities.
  • Create a new replacement terms, and update the existing term GO:0070915 (DONE)
  • lysophosphatidic acid receptor activity ; GO:0070915 (existing term)
    • New def: Combining with the phospholipid derivative lysophosphatidic acid, and transmitting the signal across the membrane by activating an associated G-protein.
    • New exact synonym: LPA receptor [PMID: 15755723]
    • New DBXrefs GOC:bf, CHEBI:52288, PMID:15755723
    • NB: Remap the following InterPro domains (previously mapped to GO:0001619) to this term:
      • IPR002277
      • IPR004065
      • IPR004066
      • IPR005385
  • sphingosine-1-phosphate receptor activity ; GO:0038036 (NEW)
    • Combining with the sphingolipid sphingosine-1-phosphate (S1P), and transmitting the signal across the membrane by activating an associated G-protein.
    • exact synonym: S1P receptor activity [Wikipedia: Sphingosine_1-phosphate]
    • GOC:bf, Wikipedia: Sphingosine_1-phosphate, Wikipedia: S1PR1, PMID: 12728273
    • NB: Remap the following InterPro domains (previously mapped to GO:0001619) to this term:
      • IPR004061
      • IPR000987
      • IPR004061
      • IPR004062
      • IPR004063
      • IPR004064
      • IPR005386

delta-opioid receptor activity ; GO:0004986 (17 manual annotations , IPR000321 mapping)
Combining with an opioid to initiate a change in cell activity, with the pharmacological characteristics of delta-opioid receptors, including the activity of enkephalins as ligands.
kappa-opioid receptor activity ; GO:0004987 (1 manual annotation, IPR000452 mapping)
Combining with an opioid to initiate a change in cell activity, with the pharmacological characteristics of kappa-opioid receptors, including high affinity for dynorphins.
mu-opioid receptor activity ; GO:0004988 (29 manual annotations, IPR000105 mapping)
Combining with an opioid to initiate a change in cell activity, with the pharmacological characteristics of mu-opioid receptors, including high affinity for enkephalins and beta-endorphin but low affinity for dynorphins.
X-opioid receptor activity ; GO:0015051 (0 manual annotations. IPR001420 mapping)
Combining with an opioid to initiate a change in cell activity, with the pharmacological characteristics of X-opioid receptors.

TODO: Replace with receptor terms for specific ligands: (OBSOLETE: NOV 14th 2011)

    • enkephalin receptor activity ; GO:NEW (related synonym: delta-opioid receptor activity)
      • Combining with an enkephalin, and transmitting the ….. An enkephalin is a pentapeptide (Tyr-Gly-Gly-Phe-Met/Met-enkephalin or Tyr-Gly-Gly-Phe-Leu/Leu-enkephalin) involved in regulation nociception in the body.
    • beta-endorphin receptor activity ; GO:NEW (related synonym: mu-opioid receptor activity)
      • Combining with beta-endorphin, and transmitting the ….. Beta-endorphin is a peptide, 31 amino acids long, resulting from processing of the precursor proopiomelanocortin (POMC).
    • morphine receptor activity ; GO:NEW (related synonym: mu-opioid receptor activity)
      • Combining with morphine (17-methyl-7,8-didehydro-4,5α-epoxymorphinan-3,6α-diol), and transmitting the ….. (CHEBI:17303)
    • dynorphin receptor activity ; GO:NEW (related synonym: kappa-opioid receptor activity)
      • Combining with a dynorphin…. A dynorphin is any opioid peptide that is generated by cleavage of the precursor protein prodynorphin.
    • EDITS TO EXISTING TERM: nociceptin/orphanin-FQ receptor activity ; GO:0001626 (Combining with the peptide nociceptin/orphanin-FQ to initiate a change in cell activity.)
      • RENAME and REDEFINE: nociceptin receptor activity ; GO:0001626 (Combining with the peptide nociceptin, and transmitting the signal.......).
      • Synonym: orphanin-FQ receptor activity
      • Synonym: OFQ receptor activity (PR:000012940)
      • Related synonym: X-opioid receptor activity
      • New parent: opioid receptor activity ; GO:0004985

natural killer cell receptor activity ; GO:0045233
A receptor found on the surface of natural killer cells which binds Class I MHC antigens and is required for activation of NK activity. It belongs to the Ly49i family.

TODO:

  • OBSOLETE (NOV 14th 2011)
    • Reason 1 for obsoletion: GO:0045233 is defined based on its location on a specific cell type, rather than what signal it transmits.
    • Reason 2 for obsoletion: The definition is misleading: there are NK cell receptors that activate NK activity, and some which inhibit NK activity (PMID 9597134).
    • Consider instead: transmembrane signaling receptor activity ; GO:0004888
    • Consider instead: natural killer cell activation ; GO:0030101
    • Consider instead: natural killer cell inhibitory signaling pathway ; GO:0002769
    • Consider instead: cell surface receptor linked signaling pathway ; GO:0007166

non-kinase phorbol ester receptor activity ; GO:0001566 
Combining with a phorbol ester and transmitting the signal by a mechanism independent of kinase activity
non-tyrosine kinase fibroblast growth factor receptor activity ; GO:0001571
platelet-derived growth factor alpha-receptor activity ; GO:0005018
Combining with platelet-derived growth factor isoform PDGF-AA, PDGF-BB or PDGF-AB to initiate a change in cell activity.
platelet-derived growth factor beta-receptor activity ; GO:0005019
Combining with platelet-derived growth factor isoform PDGF-BB or PDGF-AB to initiate a change in cell activity.

TODO:

  • This is more complicated because of the process terms. If I change these, the process/function relationships would have to be shifted up to the parent term. Or new ligand-activated signaling pathway terms created. See PMID 15207812 for an overview of PDGF and PDGFR signaling.
    • platelet-derived growth factor receptor-alpha signaling pathway ; GO:0035790
    • platelet-derived growth factor receptor-beta signaling pathway ; GO:0035791


PLC activating metabotropic glutamate receptor activity ; GO:0001639
A G-protein coupled receptor that binds glutamate and is linked to the inositol 1,4,5-trisphosphate/calcium signaling system.
(only one structured like this)
transforming growth factor beta receptor activity, type I ; GO:0005025
Combining with a complex of transforming growth factor beta and a type II TGF-beta receptor to initiate a change in cell activity; upon binding, acts as a downstream transducer of TGF-beta signals.
transforming growth factor beta receptor activity, type II ; GO:0005026
Combining with transforming growth factor beta to initiate a change in cell activity; upon ligand binding, binds to and catalyzes the phosphorylation of a type I TGF-beta receptor.
transforming growth factor beta receptor activity, type III ; GO:0070123
Combining with transforming growth factor beta to initiate a change in cell activity; facilitates ligand binding to type I and type II TGF-beta receptors.
activin receptor activity, type I ; GO:0016361
activin receptor activity, type II ; GO:0016362

For a review on PDGFR signaling, see PMID 9395284


5-HT1 receptor activity ; GO:0001586 
5-HT2 receptor activity ; GO:0001587

TODO:

  • Rename: serotonin receptor activity, coupled via Gi/Go ; GO:0001586
  • Rename: receptor activity, coupled via G11q ; GO:0001587

adrenergic receptor activity ; GO:0004935
Combining with epinephrine or norepinephrine and transmitting the signal across the membrane by activating the alpha-subunit of an associated heterotrimeric G-protein complex.
alpha-adrenergic receptor activity ; GO:0004936
Combining with epinephrine or norepinephrine to initiate a change in cell activity via activation of a G protein, with pharmacological characteristics of alpha-adrenergic receptors.

For other problematic receptor terms, search in OBO-Edit for receptor terms that have 'receptor activity' in name, and don't have a parent with 'binding' that can be reached by HAS_PART.