Talk:RECEPTORS

IP3 RECEPTOR DISCUSSION

(JUNE 2011)

Current GO structure (June 2011):
 receptor activity ; GO:0004872
  --%inositol-1,4,5-trisphosphate receptor activity ; GO:0008095
  ----%inositol 1,4,5-trisphosphate-sensitive calcium-release channel activity ; GO:0005220

 inositol-1,4,5-trisphosphate receptor activity ; GO:0008095
 DEFINITION: Combining with inositol-1,4,5-trisphosphate to initiate a change in cell activity.

 inositol 1,4,5-trisphosphate-sensitive calcium-release channel activity ; GO:0005220
 DEFINITION: Catalysis of the transmembrane transfer of a calcium ion by a channel that opens when inositol 1,4,5-trisphosphate has been bound by the channel complex or one of its constituent parts.

Q2.1: Are there any IP3 receptors that don't act as calcium channels?

Steve and Mark in Reactome-EBI don't know of any IP3 receptors that don't act as ligand-gated calcium channels. Therefore, we propose is to merge GO:0008095 and GO:0005220. The merged term would still retain a link to 'signaling' as Becky has added a P/F link:

  inositol phosphate-mediated signaling ; GO:0048016
  --[part_of] inositol-1,4,5-trisphosphate receptor activity ; GO:0008095

TRANSPORT RECEPTORS VS SIGNALING RECEPTORS DISCUSSION

The two main options to deal with the cargo/signaling receptor split were discussed at the signaling call on July 18th 2011

OPTION 1:LIMIT 'RECEPTOR ACTIVITY' TO RECEPTORS THAT SIGNAL (OPTION REJECTED)

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

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

GO:0004872 would be renamed to 'signaling receptor activity ; GO:0004872', and a comment would be added:

• 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'.
• ii. Cargo receptors do more than just bind their substrate.
• iii. Several mappings to GO:0004872 are for 'cargo receptors'.

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

  %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: [1]

  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 ligand 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 LDL signaling lipoprotein particle mediated signaling ; GO:0055095. It's not entirely clear how LDL signals here (see Ruth's comment below). It may be that it signals to intracellular cascades once it's been internalized.

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]