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[[Category:Signaling]]
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Return to Signaling Main Page [[http://wiki.geneontology.org/index.php/Signaling]]
Return to Signaling Main Page [[http://wiki.geneontology.org/index.php/Signaling]]


 
==<font color="navy"> RECEPTORS AND HAS_PART</font color> <font color="green">: STARTED </font color> ==  
 
==<font color="navy"> Receptors and HAS_PART</font color>==


There is a proposal to change the binding relationships, and kinase activities of the receptors to HAS_PART relationships.
There is a proposal to change the binding relationships, and kinase activities of the receptors to HAS_PART relationships.
Line 21: Line 20:


'''Related receptor SF item:'''
'''Related receptor SF item:'''
https://sourceforge.net/tracker/index.php?func=detail&aid=2684750&group_id=36855&atid=440764
* From Nicolas Le Novère: https://sourceforge.net/tracker/index.php?func=detail&aid=2684750&group_id=36855&atid=440764
* Adding HAS_PART relationships to receptors: https://sourceforge.net/tracker/?func=detail&aid=3103037&group_id=36855&atid=440764




* <font color="green"> 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.</font color>


==<font color="navy">TRANSMEMBRANE RECEPTORS</font color>    <font color="red">: DONE </font color> ==  
==<font color="navy">TRANSMEMBRANE RECEPTORS</font color>    <font color="red">: DONE </font color> ==  
Line 41: Line 43:




==<font color="navy">SIGNALING RECEPTORS</font color>==
==<font color="navy">SIGNALING RECEPTORS VS CARGO RECEPTORS</font color>    <font color="red">: DONE </font color> ==


There are 2 main options here:
'''BACKGROUND'''


== <font color="purple">'''OPTION 1:LIMIT 'RECEPTOR ACTIVITY' TO RECEPTORS THAT SIGNAL '''</font color> ==
* 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.


This is consistent with the parentage of 'receptor activity' in GO:
* 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'.


  signal transducer activity ; GO:0004871
* See also the [http://gocwiki.geneontology.org/index.php/Signaling_and_receptor-mediated_endocytosis receptor-mediated endocytosis] background and discussion
  --%receptor activity ; GO:0004872
* See details on the [http://gocwiki.geneontology.org/index.php/Talk:RECEPTORS#TRANSPORT_RECEPTORS_VS_SIGNALING_RECEPTORS_DISCUSSION discussion] on the cargo/signaling split.
* See Tanya's [https://sourceforge.net/tracker/?func=detail&aid=2894756&group_id=36855&atid=440764 SF item] that started the thread


A comment would be added to GO:0004872:
* The options were discussed at the signaling call on [http://gocwiki.geneontology.org/index.php/July_18th_2011 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 [http://gocwiki.geneontology.org/index.php/Talk:RECEPTORS#TRANSPORT_RECEPTORS_VS_SIGNALING_RECEPTORS_DISCUSSION discussion discussion] section). '''These edits were added to the ontology on AUGUST 2nd 2011 (revision 2.2140).'''
*Note that this term and its child terms are intended for gene products which are directly coupled to a signal transduction pathway. This term should not be used to annotate proteins that bind a signal but do not pass the signal on. For decoy receptors, mop-up receptors, adhesion receptors, importin receptors and nutrient receptors, consider instead annotating to terms under 'binding ; GO:0005488'. For ligand-activated channels, consider instead the term 'ligand-gated ion channel activity ; GO:0015276' and its children.


'''PROBLEMS/OUTSTANDING QUESTIONS WITH OPTION 1'''
* <font color="orange">PLEASE COULD THE SIGNALING WG CHECK TO SEE IF ANY RECEPTOR TERMS LOOK IN THE WRONG PLACE !!</font color>


i. Where do the other 'receptors' live? (eg decoy receptors, adhesion receptors, vitellogenin receptors etc?). They would have to be directly under 'molecular function'.


Some Notes/Outstanding Questions:


== <font color="purple">'''OPTION 2: SPLIT 'RECEPTOR ACTIVITY' INTO CARGO RECEPTORS AND SIGNALING RECEPTORS '''</font color> ==
* <font color="navy">PATTERN RECOGNITION RECEPTORS</font color>: 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).


  %receptor activity ; GO:0004872
However, given GO:0002221
  --%receptor activity involved in signal transduction ; GO:NEW1
pattern recognition receptor signaling pathway ; GO:0002221
  --%receptor activity involved in endocytosis ; GO:NEW2
--[partof]pattern recognition receptor activity ; GO:0008329


  signal transducer activity ; GO:0004871
**<font color="orange">Q1: Do we want a term 'signaling pattern recognition receptor activity ; GO:NEW'? to be under GO:0002221 instead?</font color>
  --%receptor involved in signal transduction ; GO:NEW1
**<font color="orange">Q2: Are any of the current children of GO:0008329 signaling receptors?</font color>


  receptor-mediated endocytosis
  --<receptor activity involved in endocytosis ; GO:NEW2


* <font color="navy">LIPOPROTEIN PARTICLE RECEPTORS</font color>. 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.


'''PROBLEMS/OUTSTANDING QUESTIONS WITH OPTION 2''


i. How do you define a generic 'receptor' to distinguish it from 'binding'? Some suggested definitions are below:
* <font color="navy">APOLIPOPROTEIN RECEPTORS</font color>. 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.


  receptor activity
**<font color="orange">Q: Do we need to create 'apolipoprotein cargo receptor' and 'apolipoprotein signaling receptor' terms.</font color>
  Combining selectively with a extracellular or intracellular molecule to initiate a change in cell state or activity.


  receptor activity involved in signal transduction ; GO:NEW
  exact synonym: signaling receptor
  Combining selectively with an extracellular or intracellular signal, and transmitting the signal to initiate a change in cell state or activity.
  Comment: Note that this term and its child terms are intended for gene products which are directly coupled to a signal transduction pathway. In addition, this term should not be used to annotate proteins that bind a signal but do not  pass the signal on.


  receptor activity involved in endocytosis ; GO:NEW
  exact synonym: cargo receptor
  exact synonym: endocytic receptor
  Combining selectively with an extracellular molecule or substrate, and delivering the cargo into the cell via endocytosis. [PMID 12827279]


==<font color="navy">X-ACTIVATED RECEPTORS</font color> <font color="green">: STARTED </font color> ==


ii. What about receptors that transmit a signal AND endocytose? E.g. Ligand-activated EGFR undergoes endocytosis, and there is the possibility that activated receptors organise their own endocytosis.
*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'.


iii. Given its current definition, can 'transmembrane receptor activity' be limited to signaling receptors? The non-signaling receptors would need to move out from under 'transmembrane receptor activity'. Would we want to distinguish between TM and non-TM endocytic receptors? I don't think it's a useful distinction.
  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


* <font color="orange"> Q: Which of  the following are signaling receptors?</font color>


* This ties in with the receptor-mediated endocytosis discussion: [http://gocwiki.geneontology.org/index.php/Signaling_and_receptor-mediated_endocytosis]
* <font color="green">: STARTED Started (Aug 16th 2011, revision 1.2184) changing the TM growth factor receptors to X-activated receptor activity. </font color>


  asialoglycoprotein receptor activity ; GO:0004873
  The mediation of the endocytosis of plasma glycoproteins from which the terminal sialic acid residue on their complex carbohydrate groups has     
  been removed; recognizes the terminal galactose and N-acetylgalactosamine units;
  the complex of receptor and ligand is internalized and transported to a sorting organelle where disassociation occurs,
  the receptor being recycled to the cell membrane.


<font color="grey">Based on the Feb discussions I think this is the transport type of receptor with minimal signaling, only signaling to stimulate endocytosis [RL]</font color>


  axon guidance receptor activity ; GO:0008046
  Combining with an extracellular messenger that results in a change in cellular activity involved in axon guidance.
<font color="grey">yes this stimulates a signaling pathway see PMID 15107857 [RL] Should there be more specific terms here, similar to the cytokine receptor activity child terms?  With the availability of column 16 maybe not [RL].</font color>


netrin receptors are often involved in axon guidance, but they also have additional non-neuronal roles (PMID 20108323, PMID 19785719). I suggest GO:0008046 is changed to 'receptor activity involved in axon guidance' [RF].


  complement receptor activity ; GO:0004875
==<font color="navy"> LIGAND-GATED ION CHANNELS</font color>==
  Combining with any component or product of the complement cascade to initiate a change in cell activity.\
<font color="grey">yes this stimulates a signaling pathway see PMID 11884446 [RL]</font color>


  scavenger receptor activity ; GO:0005044
  Combining with acetylated low-density lipoproteins, advanced glycation end products, or other polyanionic ligands to initiate a change in cell activity.
  (PMID 20981357 shows that scavenger receptors can act as transport receptors OR signaling receptors [RF]


    vitellogenin receptor activity ; GO:0008196
<font color="orange">Q: Are ligand-gated ion channels, receptors, and if so should they be in the receptor node?</font color>
    Combining with vitellogenin to initiate a change in cell activity.
    (PMID 12429745 suggests this is a receptor involved in endocytosis)


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


* <font color="orange">Q3: How do the LDL receptors work?</font color>
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)


  receptor activity ; GO:0004872
  --%transmembrane receptor activity ; GO:0004888
  ----%lipoprotein particle receptor activity ; GO:0030228
  ------%high-density lipoprotein particle receptor activity ; GO:0070506
  ------%low-density lipoprotein receptor activity ; GO:0005041
  ------%very-low-density lipoprotein particle receptor activity ; GO:0030229


  signal transduction ; GO:0007165
<font color="purple">'''IP3 RECEPTOR'''</font color>
  --%lipoprotein particle mediated signaling ; GO:0055095
  ----%high density lipoprotein particle mediated signaling
  ----%low-density lipoprotein particle mediated signaling


* The following two papers suggest that LDLRs have roles in signaling, independent of their roles in endocytosis. The mechanism by which they signal is still up for debate, but LDL binding may trigger cleavage of the receptor, which releases an intracellular domain that may (via adaptor proteins) regulate transcription.
There was [http://wiki.geneontology.org/index.php/Talk:RECEPTORS 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).
**PMID 12671190
**PMID 19401589
* This type of LDLR signaling seems independent of any intracellular LDL signaling which would occur once LDL has been endocytosed into the cell




<font color="grey">Steve Humphries and Philippa Talmud have confirmed that lipoprotein particle receptor activity is a transport step not 'signaling'. All downstream effects mediated by changes in intracellular cholesterol --> membrane changes --> flip in out and release of transcription factors etc.
<font color="purple">'''IONOTROPIC RECEPTORS'''</font color>
Ref PMID 16013438 suggests that LDL can act as a hormone, stimulating cell migration, However, PMID 21329689 suggests LDL signaling via activation of TLR4-dependent intracellular signaling pathways. As TLR4 signaling is usually considered as starting intracellularly, then LDL may be having an effect once it is in the cell rather than via the LDLreceptor involved in its endocytosis.  So I think the lipoprotein transmembrane receptors are involved in transport. We may have to look at the naming of possible intracellular receptors, but these may recognise the 'lipids' rather than the lipoprotein particles. Which also implies that we need to reexamine lipoprotein particle signaling in the future. [RL]</font color>
 
Are 'ionotropic receptors' just ligand-gated ion channels? If so, there is redundancy between:


==<font color="navy">X-ACTIVATED RECEPTORS</font color>==
  glutamate-gated calcium ion channel activity ; GO:0022849
  &
  ionotropic glutamate receptor activity ; GO:0004970


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


  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




==<font color="navy"> GPCRs</font color>==
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 <font color="red">: DONE </font color> ==
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.
==<font color="navy"> DODGY RECEPTOR TERMS</font color>==
* 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.
<font color="green">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</font color>
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.
<font color="green">DONE:
* Merged into parent: endothelin receptor activity ; GO:0004962'.</font color>
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.
<font color="orange">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. [http://en.wikipedia.org/wiki/AMPA_receptor]. 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.</font color>
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.
<font color="purple">TODO:
There are many high/low affinity transport and transporter terms in GO. Leave these for the moment.</font color>
lysosphingolipid and lysophosphatidic acid receptor activity ; GO:0001619
Combining with lysosphingolipid or lysophosphatidic acid to initiate a change in cell activity.
<font color="purple">TODO:
* OBSOLETE (Nov 14th 2011). Reason: This term represents two separate activities</font color>.
* <font color="green">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
</font color>
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.
<font color="purple">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
</font color>
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.
<font color="purple">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
</font color>
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.


==<font color="navy"> LIGAND-GATED ION CHANNELS</font color>==
<font color="orange">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</font color>




<font color="orange">Q: Are ligand-gated ion channels, receptors, and if so should they be in the receptor node?</font color>
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)


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


ligand-gated ion channel activity ; GO:0015276 (synonym [NARROW] :ionotropic neurotransmitter receptor
transforming growth factor beta receptor activity, type II ; GO:0005026
extracellular ATP-gated cation channel activity ; GO:0004931 (synonym [RELATED]: P2X receptor)
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.
inositol 1,4,5-trisphosphate-sensitive calcium-release channel activity ; GO:0005220 (see below)


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.


<font color="purple">'''IP3 RECEPTOR'''</font color>
activin receptor activity, type I ; GO:0016361
activin receptor activity, type II ; GO:0016362


There was [http://wiki.geneontology.org/index.php/Talk:RECEPTORS 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).
<font color="purple">For a review on PDGFR signaling, see PMID 9395284</font color>




<font color="purple">'''IONOTROPIC RECEPTORS'''</font color>
5-HT1 receptor activity ; GO:0001586
5-HT2 receptor activity ; GO:0001587


Are 'ionotropic receptors' just ligand-gated ion channels? If so, there is redundancy between:
<font color="purple">TODO:
* Rename: serotonin receptor activity, coupled via Gi/Go ; GO:0001586
* Rename: receptor activity, coupled via G11q ; GO:0001587
</font color>


  glutamate-gated calcium ion channel activity ; GO:0022849
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.
  ionotropic glutamate receptor activity ; GO:0004970
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 a background, see http://www.sinauer.com/neuroscience4e/animations5.3.html.
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.

Latest revision as of 17:19, 10 July 2014

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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.