RECEPTORS: Difference between revisions

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


i. How do you define a generic 'receptor' to distinguish it from 'binding'?
i. How do you define a generic 'receptor' to distinguish it from 'binding'? Some suggested definitions are below:


   receptor activity
   receptor activity
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   exact synonym: signaling receptor
   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.
   Combining selectively with an extracellular or intracellular signal, and transmitting the signal to initiate a change in cell state or activity.
   Comment:  
   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
   receptor activity involved in endocytosis ; GO:NEW
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ii. What about receptors that transmit a signal AND endocytose? E.g. Ligand-activated EGFR undergoes endocytosis.
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.


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?
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.
   
   



Revision as of 12:53, 28 June 2011

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Receptors and HAS_PART

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: https://sourceforge.net/tracker/index.php?func=detail&aid=2684750&group_id=36855&atid=440764


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

There are 2 main options here:

OPTION 1:LIMIT 'RECEPTOR ACTIVITY' TO RECEPTORS THAT SIGNAL

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

  signal transducer activity ; GO:0004871
  --%receptor activity ; GO:0004872

A comment would be added to GO:0004872:

  • 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

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


OPTION 2: SPLIT 'RECEPTOR ACTIVITY' INTO CARGO RECEPTORS AND SIGNALING RECEPTORS

  %receptor activity ; GO:0004872
 --%receptor activity involved in signal transduction ; GO:NEW1
 --%receptor activity involved in endocytosis ; GO:NEW2
 signal transducer activity ; GO:0004871
 --%receptor involved in signal transduction ; GO:NEW1
 receptor-mediated endocytosis
 --<receptor activity involved in endocytosis ; GO:NEW2


'PROBLEMS/OUTSTANDING QUESTIONS WITH OPTION 2

i. How do you define a generic 'receptor' to distinguish it from 'binding'? Some suggested definitions are below:

 receptor activity
 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]


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.

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.


  • Q: Which of the following are signaling receptors?
  • This ties in with the receptor-mediated endocytosis discussion: [2]
  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.

Based on the Feb discussions I think this is the transport type of receptor with minimal signaling, only signaling to stimulate endocytosis [RL]

  axon guidance receptor activity ; GO:0008046
  Combining with an extracellular messenger that results in a change in cellular activity involved in axon guidance.

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].

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
  Combining with any component or product of the complement cascade to initiate a change in cell activity.\

yes this stimulates a signaling pathway see PMID 11884446 [RL]

  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
   Combining with vitellogenin to initiate a change in cell activity.
   (PMID 12429745 suggests this is a receptor involved in endocytosis)


  • Q3: How do the LDL receptors work?
  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
  --%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.
    • 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


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. 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]

X-ACTIVATED RECEPTORS

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


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.