A number of studies have provided circumstantial evidence of an EET receptor, such as many EET actions requiring GalphaS, ADP ribosylation, membrane impermeable EET analogues having actions at the cell surface, candidate high affinity binding proteins expressed at the cell surface etc. So why after so many years of EET research have still not definitively demonstrated its existence?
I may tell my recent experience with a receptor that is, similarly, not yet accepted despite circumstantial evidence. First of all I consider that radioligand binding is totally required to be sure of receptor deorphanization. In the case of this specific receptor (not EET but the one I have followed recently) the binding was performed by one laboratory. IUPHAR recommendation for GPCRs is that two labs report similar (strong, i.e. by binding) evidence. On the other hand I have checked the binding data and all other "evidence" and I am not convinced that the endogenous molecule is the readl agonist and therefore I applaude IUPHAR decision of wait and see (despite there are hundred papers assuming that the receptor is indeed deorphanized).
I am not familiar at all with eicosatrienoic and less with
I really wanted to commit myself full-time a few years back to find this as it seems they are so close to identifying the EET receptor but a few things kept us from committing ourselves full-time to the project. The major reason being some very talented labs and people already worked so hard to find this using the typical conventional approaches such as pull-down assays, flow gating methods as well as screening over 100 GPCRs.
In short, a few people told us that they were able to identify a target GPCR but when they expressed the receptor in HEK cells and ran a competitive ligand assay, it exhibited micromolar affinity. I think there is some subtle complexity that has prevented its identification such as heterodimerization with another GPCR, some sort of GPCR interaction protein or maybe even a lipid raft or caveolin requirement.
Thank you Daniel.
When asking this question (in my head for years, and here) I wondered why have we known about many receptors for decades and yet in the modern era we can't identify this one. I guess that may be naivety on my part.
Yes definitely glad to share. It has been something on my mind as well the last four years. I hope someday we can figure it out as it would be an invaluable target for the cardiovascular and stroke fields of research. I know this is still an active area of research pursued by many of the same groups that have published on the subject. I know Shunck's group out of Germany is still actively investigating it so hopefully we will know soon!
I think that when you consider the cell surface related actions of EETs and their analogues, as well as membrane permeable vs impermeable antagonist actions (EEZE vs EEZE-mSl, for example), it points there perhaps being more than one type of receptor
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