Simplifying receptor theory and what are inverse/silent agonists

[DJHENRU]

This is a thread dedicated to a question, "can anyone explain, or link to better information on receptor theory than the Wikipedia page?" It explains in a fascinating way about how the scientific method came to prove it, but no links

My problem when overviewing was I thought, it too overtly was about proving the explanation of of how receptors came to be understood. This isn't incorrect for scientific explanation of theory! I just cannot assimilate knowledge easily coming from an approach of pharmacology via psychoactives affecting receptors.
I barely just learned just recently only having an understanding the idea of inversive & silent agonists.

I guess this isn't even a complete request at information of wanting to better learn of how the neuron came to known to be structured.

This could be basic drug discussion worthy, they explained some statistic driven data to me very well.
It could be blog worthy if a mod thinks this is a messy shot at nothing, loaded with all sorts of personal bias that very well drugs play a role in why I couldn't sink my teeth into maybe the MOST definitive & simplified metatheory.

 

[sekio]

You probably don't want to be reading about "receptor theory", it sounds like you want to read a molecular biology textbook, in particular the section on G-protien coupled receptors.

The TL;DR version is that a large portion of "receptors" are blobs of protien that are linked to other blobs of protien, and chemicals will bind to one of the blobs and make it change shape (receptor activation), changing the shape and therefore the function of other protiens attached to it (downstream effects). The important thing to remember is that most receptors can be turned quite a few ways (functional selectivity, see 5HT2A), and there are drugs that bind to a receptor but *don't* make it change shape (silent/neutral antagonists), or make it change shape the "opposite way" (inverse agonist).

If you want to know more about the overall structure of the neurone & synapse, I strongly suggest a text like Molecular Biology of The Cell. For slightly lighter reading, use the BL searche engine and read some of the stuff on G-protien receptors.



see also
http://www.bluelight.ru/vb/threads/166687-Erowid-BlueLight-Neuropharmacology-Text
http://www.bluelight.ru/vb/threads/354683-A-Lesson-on-Ligand-Receptor-Interactions

 

[Black]

i don't know what you were reading but wikipedia's Agonist and Antagonist pages explain it quite well imho.

basically a drug has two important qualities for interacting at a receptor: affinity, which is a measure of how tightly it binds to the receptor and efficacy, which says how strong of an effect is resulting from binding of the drug. there's a continuum from
- greater activation than the endogenous ligand (super agonist) over
- the same effect as the endogenous ligand (full agonist) over
- weaker activation (partial agonist) than the endogenous ligand over
- no activation ( (silent) antagonist) to
- less activation than without any ligand (inverse agonist).

the latter is possible because there's always a little bit of activation even when no agonist is bound to the receptor. you can have a drug that silences this intrinsic activity.

another important point is where the drug binds at the receptor. it can bind in the same site and therefore compete in binding with the main ligand, or it can bind at another site and modulate (positively or negatively) the activation pattern of the receptor. this would be called an allosteric modulator.


i think that's the most important information about drug-receptor-binding in short form, it hope that helps understand the whole thing.

 

[ebola?]

- greater activation than the endogenous ligand (super agonist) over
- the same effect as the endogenous ligand (full agonist) over
- weaker activation (partial agonist) than the endogenous ligand over
- no activation ( (silent) antagonist) to
- less activation than without any ligand (inverse agonist).

And as continued research into the 5ht2a receptor is demonstrating, you can have activation that elicits secondary messaging that's just qualitatively distinct from the endogenous ligand. I don't think this fits in particularly well into the continuum.

ebola

 

[Black]

And as continued research into the 5ht2a receptor is demonstrating, you can have activation that elicits secondary messaging that's just qualitatively distinct from the endogenous ligand. I don't think this fits in particularly well into the continuum.

ebola

i was just trying to distill the most important points into a few paragraphs, without going into detail too much.

do you mean that a ligand at 5-ht2a can activate a signalling pathway, that 5-ht doesn't activate at all? if yes, i'd be interested in further info. i only know of the differential activation of various partial agonists concerning the pla2 and and plc pathways. in that case you'd have one "continuum" for each signalling pathway. i guess i have missed some of the more interesting papers in the last few years .

 

[ebola?]

do you mean that a ligand at 5-ht2a can activate a signalling pathway, that 5-ht doesn't activate at all?

Yeah. It's my understanding that serotonin itself doesn't activate messaging via PLA2---->arachidonic acid, but my understanding was gleaned from statements by trusted members here, not direct understanding of relevant research. Someone who knows more should chime in.

ebola

 

[Black]

i did some further reading yesterday and this paper shows serotonin activating the pla2->aa pathway (look at fig. 5 for a nice graph).

i've also found this paper, which might be more like it, but we still can't know as they didn't compare to serotonin itself. i didn't read the whole thing and didn't understand all of what i read, but it surely looks like they stumbled on something interesting.

 

[ebola?]

Okay. Looks like I was mistaken, but it also looks like serotonin itself is somewhat selective for the PLC pathway. The mystery continues to unfold.

ebola

 

[Epsilon Alpha]

Any love for receptor tyrosine kinases? Ion channels, nuclear receptors? Any interest in those receptor families?

 

[ebola?]

er...yeah, aren't most pharmacologists polyamorous in this respect?

ebola

 

[Grand Touring]

Let's also not forget that an inverse agonist not only exists in a way already mentioned, but a result from the opposite of the completed agonist effect. The best example I can think of right now, is let's say, the mu opioid receptor. The completed agonist effect binds with varying degrees of affinity and efficacy, with a result of psychotropic analgesia. The inverse is always used in situations to prevent or deal with an overdose, putting someone in a position completely opposite of a full or partial agonist--which in this case is either complete or precipitated withdrawals when the MOR is already fulfilled. Those of you with opiate experience would know this to be naltrexone, which is more correctly a partial inverse agonist.

 

[Sturnam]

Any love for receptor tyrosine kinases?...... nuclear receptors? Any interest in those receptor families?

Probably less interest from people here, as those wouldn't be psychoactive.

Although there is definitely some differential trafficking for TrkB (BDNF), so I'm sure they would have the same type of functional selectivity that GPCRs do. Especially nuclear hormones, I bet that different protein interactions mediates the various gene expression changes.

Retrograde neurotrophin signaling: Trk-ing along the axon.

Target-derived neurotrophins are required for the growth and survival of innervating neurons. When released by postsynaptic targets, neurotrophins bind receptors (Trks) on nerve terminals. Activated Trks signal locally within distal axons and retrogradely through long axons to distant cell bodies in order to promote gene expression and survival. Although the mechanism of retrograde neurotrophin signaling is not fully elucidated, considerable evidence supports a model in which the vesicular transport of neurotrophin-Trk complexes transmits a survival signal that involves PI3K and Erk5. Other, non-vesicular modes of retrograde signaling are likely to function in parallel. Recent studies highlight the importance of the location of stimulation as a determinant of Trk signaling. Defects in signaling from distal axons to cell bodies may be causally related to neurodegenerative disorders.

http://www.ncbi.nlm.nih.gov/pubmed/12049932