agonist directed trafficking

[EN21]

First I must admit, that I don´t know much about neurophysiology.
I have got a question concerning the agonist directed trafficking: How can I imagine this? Is it right that it means that two different agonists with the same affinity to a GPCR subtype can produce different effects to the cell? So how can this be possible at the same receptor subtype? The logical consequence would be to me, that there are different binding sited on the same receptor subtypes, or are there more only slightly different receptor subtype - subtypes? I hope that it is possible to understand what I mean.

 

[BilZ0r]

The exact mechanism still isn't known. As far as I am awear, there are two theories, one is that different agonists bind to receptor X when it is in two different positions Active position 1 (R*1) and active position 2 (R*2). It turns out the R*1 and R*2 have different affinities for different G-proteins, Gs vs G13 etc... this allows different ligands to activate different 2nd messanger systems differeing amounts.

I think the other theory goes that there are physically disparate receptor populations which bind different 2nd messangers (glycolylation, palmytoylation, myristoylation???) and have different affinities for ligands.

There was this paper that was used as evidence to support the 2nd theory... however I don't buy it.

 

[EN21]

Thank you for the prompt answer!
My next question is: Is there a consequence for antagonists? Can different antagonists with same Ki value at a specific receptor subtype also block diferent pathways?

 

[BilZ0r]

Well when you say subtypes, do you subtypes, or do you mean 2nd messanger cascades? The answer is yes either way... in that paper by nichols I cited above, they use an irreversible antagonist, and it has blocked essentially all of one 2nd messanger cascade before the concentration gets high enough to block the other cascade.

 

[Smyth]

BilZ0r you have a habit of spelling aware "awear". Im not saying this to be funny but I find it slightly annoying.

 

[BilZ0r]

Yup, I sure do, I hate english, it's such a fucking stupid language... If it was spelt aware it should be said ah-wayr. Which it isn't.

 

[EN21]

Very interesting!
I meant the blocking of a single second messenger cascades within one receptor subtype e.g. the D1.
I think this would be conform with your answer.
Thanks!

 

[BilZ0r]

This came from an article in the most recent Trends in Pharmacological Sciences

Trends in Pharmacological Sciences
Volume 26, Issue 12 , December 2005, Pages 625-630

Physiological relevance of constitutive activity of 5-HT2A and 5-HT2C receptors

Kelly A. Berga, John A. Harveyb, Umberto Spampinatoc and William P. Clarkea,

It is well known that proteins can adopt a large (perhaps infinite) number of conformations and it is likely that more than one of these states is active. It is also now generally accepted that individual 7TM receptors couple to multiple signaling systems in cells. Moreover, it is becoming clear that different agonists, acting at the same receptor, can elicit different cellular signaling profiles, a process that has been termed ‘agonist-directed trafficking of receptor stimulus’ 41 and 42 or ‘functional agonist selectivity’ [43]. The most widely accepted mechanistic view is based on the notion that receptors can adopt multiple active conformations (e.g. R*, R** and R***) that have different capacities to activate each of multiple signaling systems coupled to a receptor. Ligands, with different affinities for these active conformations (e.g. KA*, KA** and KA***) relative to inactive conformations (KA), would differentially bind to, and thereby enrich or deplete, certain receptor conformations, leading to ligand-specific responses as a result of activation of a single receptor subtype (Figure II).