Agonists which cause irreversible covalent bonding

[MurphyClox]

Sure, but I'd say from the info known it's not any more more neurotoxic than the likes of amphetamine, which phosphorylate the receptor binding sites which make them have to be 'internalized': that is, destroyed by the body to create a new receptor life cycle. Essentially the same process.

Yeah, maybe it's essentially the same but the irreversible ligands are much more efficient IMO. Don't underestimate that!

The half-life of a GPCR can't be answered this easy. Reasons for internalization include the aforementioned (over)stimulation of the said receptor. Please note that in such cases the receptor doesn't have to be rebuild de novo, but is recycled. This is much more economically for a cell.
In case of overstimulation by a covalent ligand, I bet that this is different (and thus, more costly in terms of ATP-use), because the covalently labeled amino acid would have to be cut out, for which there are no specific tools. Of course, there are endopeptidases (peptidases which cut somewhere in the middle of a protein strand; in contrary to exopeptidases which cut from one of the ends) but there is no mechanism for specifically detecting the 'damaged' site within a protein. With DNA this is possible (...but this is a completely different macromolecule).

I would roughly guess, that the halflife (...positioned at the cell membrane) is something in the range of minutes (1, 5, 10, 30... no exact idea). The density of receptors is in constant flow, like most processes in living organisms.

Murphy

 

[dread]

Did you know, the government puts covalent-bond forming full opioid antagonists on confiscated smack and then puts it back to circulation, aiming to deactivate the receptors of smackheads?

(Yes this is complete bullshit. I just wanted to see if I can create an urban myth)

 

[nuke]

Also, is receptor internalization the way in which cell downregulate receptors? I guess I never put two and two together until now.

Are there any studies of neurons or other cells in which irreversible receptor ligands are administered and then the cell examined after an extended period of time to see if it would internalize the receptor? There may be some sort of mechanism by which a cell can tag and send a broken receptor off to the lyzosome, and then replace them.

 

[Hammilton]

Also, is receptor internalization the way in which cell downregulate receptors? I guess I never put two and two together until now.

Yes, it's definitely part of it. I don't think it's all of it though.

 

[Nagelfar]

Yes, it's definitely part of it. I don't think it's all of it though.

Yes downregulation would also have to include more of the slowing of the process to replenishing the amount of receptors after the internalization I'd think? I wonder: is it then an indirect correlation, that the amount of internalization is inversely proportional to the regulation (i.e. creating downreglation) of receptors? If there were a binding chemical that *didn't* result in the receptor being internalized, would it prevent short or long term (or both) downregulation?

 

[inverse_agonist]

Receptors can be desensitized by (de)phosphorylation or uncoupling from their effectors (e.g., G proteins). Agonist-stimulated internalization is definitely part of downregulation, but genetic regulation has a lot to do with it, too. Oftentimes, chronic treatment with an agonist of a receptor will cause a decrease in the amount of mRNA encoding that receptor (depending on the receptor/brain region).