Ways to slow down receptor down-regulation?

[bluecross]

I'm not using things but trying to figure sth. out.

Is there a drug that could make receptor (e.g. for opiate, endorphin etc.)down regulation that say happens in 3 hours, happen in 9 hours?

 

[ebola?]

Technically, downregulation technically occurs within minutes, but it takes a while for downregulation to accrue enough to be noticeable.

ebola

 

[.:Holy::Toast:.]

The only drugs which could slow downregulation would be ones which cause receptor antagonism, but this would also negate the effect of your particular drug to an appreciable degree, and I wouldn't recommend it as I can't vouch for its safety.
I can't see why it would be dangerous but it very well could be, always air on the side of caution

 

[tyrael]

The only drugs which could slow downregulation would be ones which cause receptor antagonism....

Maybe no drugs which are commercially available however there are other drug classes which may prevent down-regulation of cell receptor sites. Basically what you're asking is how can we inhibit a cell from endocytosis - and subsequent phagocytosis - of the integral membrane protein/receptor (called tachyphylaxis)? It would be difficult (and I'd guess treatment would have to be continual) since the body would continual try to go back to homoeostasis. However, I can think of a few points along the signalling cascade which could be targeted; blocking/addition of hormones (an example being insulin on cells; an increase release of causing increased RNA transcription and translation creating new receptors and ultimately increased uptake of activated glucose into the cell), regulation (up or down) of gene expression (for said receptor protein), kinasing/phosphatasing agents (I'm thinking one of the 2nd signal transduction messengers; PKA/PKB/etc. or possibly cAMP/cGMP decomposition, PDE's), and I'm sure there's more.

In medicine, there are techniques used to prevent/slow tachyphylaxis, but they involve what you're suggesting. They're more like, say, the rotation of different opiates which target different opioid-receptors yet still provide analgesia.

An interesting article I just came across, "GABAB receptor activation protects GABAA receptor from cyclic AMP-dependent down-regulation in rat cerebellar granule cells".

Tbh the process of tachyphylaxis really isn't that well understood yet.


Edit: In fact there are already known chemicals which are used academically - Cycloheximide, which inhibits translocation in protein synthesis. Used in vitro as its teratogenic.

The processes of metabolism (biosynthesis and degradation) of mAChR seem to involve microtubular systems but not microfilament systems. Our previous results showed that the microtubular system present inside or around the plasma membrane, but not the microfilament system, participates in the accelerated degradation of mAChR (Higuchi et al., 1982). In the present study the recovery of mAChR was inhibited by the antimicrotubular agents colchicine and vinblastine, but not by the antimicrofilament agent cytochalasin B. These results suggest that microtubules, but not microfilaments, are involved in intracellular transport of mAChR.
......
We have already reported that removal of Ca 2 + with 5 mM EGTA from the culture medium reduced the agonist-induced acceleration in the degradation of mAChR (Takeyasu et al., 1981). These findings suggested that the biosynthesis and degradation of mAChR are both Ca 2 +-requiring processes.
......
The recovery of mAChR from its down-regulation was dependent on protein synthesis and was inhibited by the above agents affecting membrane protein synthesis. It was likely that this recovery of mAChR reflects the de novo synthesis of mAChR as with other membrane receptors. The above data can be of use for elucidating the regulatory mechanisms of biosynthesis of mAChR....

- Recovery of the muscarinic cholinergic receptor from its down-regulation in cultured smooth muscle

 

[tyrael]

Some information regarding general receptor regulation....

The regulation of adrenergic receptors by agonists (desensitization) appears to be a multistep process that involves several discrete events, including the rapid phosphorylation of receptors; the sequestration of the receptor in a cellular compartment not readily accessible from outside the cell; the uncoupling of the receptor, so that ligand binding still occurs but second-messenger formation is decreased; and the internalization of the receptor to intracellular sites. Persistent exposure to agonist can also result in an actual loss of receptors, presumably through degradation, but this type of receptor down-regulation occurs more slowly. Susceptibility to these agonist-promoted events differs among the various types and subtypes of adrenergic receptors.
.....
There is a high degree of polymorphism at certain loci in β2-adrenergic receptors.41 Of particular interest is a polymorphism that converts arginine to glycine at codon 16 and is substantially more prevalent in patients who have a history of nocturnal asthma.42 In experimental systems, receptors with this polymorphism are more sensitive to down-regulation in response to adrenergic agonists.43 It is intriguing to speculate that this phenotype in vivo predisposes patients to the loss of β-adrenergic function and to nocturnal asthma. Other recent data suggest that the substitution of glutamic acid for glutamine at codon 27, which yields a receptor that has decreased down-regulation, is associated with a decrease in bronchoconstriction.

- Adrenergic Receptors — Evolving Concepts and Clinical Implications, Paul A. Insel, M.D. N Engl J Med 1996; 334:580-585, February 29, 1996 DOI: 10.1056/NEJM199602293340907