Question About "Receptors"

Acarpous

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I am curious why people on this forum continue to use the term "receptor" when referring to physiological processes at the cellular. I can appreciate the fact that the literature is saturated by the metaphor, making it challenging to change the vernacular of subsequent discussions into more meaningful terms, and that Ling's work is beyond the immediate comprehension of most people (I don't understand it at the moment), but RP is exceedingly clear and consist that the metaphor is "fundamentally wrong" (Thyroid, insomnia, and the insanities) and "is still having a radically stupefying effect on biology and medicine" (Preventing and treating cancer with progesterone). So I am wondering why people here seem to use it so consistently and apparently with the intent of referring to biological processes.
 

Constatine

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I am curious why people on this forum continue to use the term "receptor" when referring to physiological processes at the cellular. I can appreciate the fact that the literature is saturated by the metaphor, making it challenging to change the vernacular of subsequent discussions into more meaningful terms, and that Ling's work is beyond the immediate comprehension of most people (I don't understand it at the moment), but RP is exceedingly clear and consist that the metaphor is "fundamentally wrong" (Thyroid, insomnia, and the insanities) and "is still having a radically stupefying effect on biology and medicine" (Preventing and treating cancer with progesterone). So I am wondering why people here seem to use it so consistently and apparently with the intent of referring to biological processes.
Because it is the language used in studies and when we refer to a study we only have their words to go by. Thus we end up just saying "receptors" while knowing this bit is not completely right.
 

Dante

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I am curious why people on this forum continue to use the term "receptor" when referring to physiological processes at the cellular. I can appreciate the fact that the literature is saturated by the metaphor, making it challenging to change the vernacular of subsequent discussions into more meaningful terms, and that Ling's work is beyond the immediate comprehension of most people (I don't understand it at the moment), but RP is exceedingly clear and consist that the metaphor is "fundamentally wrong" (Thyroid, insomnia, and the insanities) and "is still having a radically stupefying effect on biology and medicine" (Preventing and treating cancer with progesterone). So I am wondering why people here seem to use it so consistently and apparently with the intent of referring to biological processes.
I had kind of a similar question a few months ago when I stumbled on to RP ( it was when I found that a 5AR steroid happens to interact with an estrogen receptor hence wikipedia calling it an as estrogen but it doesn't show typical estradiol like properties)
I am not a researcher nor i have an electron micrograph but I think that "receptors" are real .
They are proteins that happen to react with the drugs and cause downstream actions. However , a compound action isn't limited to its interaction with a single protein as a receptor is supposed have a many-many relation i.e many compounds can react with a same protein and produce different reactions. Hence we see the terms like "agonist", "antagonist" and "inverse agonist" for a particular receptor. A drug's cumulative action might be the sum of actions with the known "receptors" + unknown "receptors" + <some magic that i have no idea of>
A lot of receptors have been supposedly identified and sequenced so I think these proteins are not completely fake and illusionary.
There are people like @Travis or kyle_m on this forum who know about this stuff a lot better than me. Hopefully , they will reply.
As for why people use the word "receptors" on this forum , as @Constatine said we only happen to go by the study conventions. Now , one would have to come up with up a new theory/hypothesis for explaining drugs and neurotransmitters actions if you drop the receptor theory. Harold Hillman has proposed such a hypothesis but I have not read it so can't comment further.
 
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Diokine

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The word "receptor" is a convenient way to get across the idea of a structure in the cell that responds to some stimulus (ligand.) There is a problem in treating these structures as "lock and key," or like lego pieces that fit together when they have the correct shapes. The problem is exacerbated by images showing ligands apparently "stuck" to the receptor site on a cell.

Receptors are more like antenna in a cell. They are electronic resonant structures built out of protein-lipid interfaces, and the various ligands influence them through subtle changes in electronic timing. Sometimes the between the receptor and ligand is so high that, like magnets, they effectively become "stuck" to each other. Often times though, only the close proximity of a ligand to a receptor is enough to trigger effects. Of course, the presence of other ligands and the local electronic environment is going to greatly influence the eletctromagnetic effects they have on one another.
 

Pointless

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I am curious why people on this forum continue to use the term "receptor" when referring to physiological processes at the cellular. I can appreciate the fact that the literature is saturated by the metaphor, making it challenging to change the vernacular of subsequent discussions into more meaningful terms, and that Ling's work is beyond the immediate comprehension of most people (I don't understand it at the moment), but RP is exceedingly clear and consist that the metaphor is "fundamentally wrong" (Thyroid, insomnia, and the insanities) and "is still having a radically stupefying effect on biology and medicine" (Preventing and treating cancer with progesterone). So I am wondering why people here seem to use it so consistently and apparently with the intent of referring to biological processes.

It doesn't look like Peat is actually addressing receptors in those passages you quotes, but the deterministic mechanical model of the cell especially its membrane. Peat has used the word receptor before to explain concepts, usually in quotes or explained with something like "what is called a".

In fact, I haven't been able to find out what Ray Peat thinks receptors are and how they work or function. Could anyone explain this to me? (I think there's a thread for this where the answer is hinted at but not with clarity)
 

Luna

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Is there such thing as Serotonin Receptors to Ray Peat?, to Haidut?, to Ling?, to Tyw?, to Peat Forum Members in general?
 

Dhair

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Is there such thing as Serotonin Receptors to Ray Peat?, to Haidut?, to Ling?, to Tyw?, to Peat Forum Members in general?
Ray believes the whole cell is the "receptor." I can't find any quote that elaborates on this, but basically it seems like he doesn't think it's useful to use the word receptor at all.
 

Kyle M

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There isn't a developed alternative theory and especially vernacular for what to call signaling molecules and the one or more signal receiving molecules that work together. There's just a lot of evidence that the underlying ideas of receptor biology are bunk
 

Dante

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There's just a lot of evidence that the underlying ideas of receptor biology are bunk
But haven't they been separately identified /isolated and sequenced ?
Incomplete I can understand but bunk - could you elaborate your experience ?
For example blocking the so called AR (androgen receptor) or AR antagonist stops MPB .
 

Luna

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Are reuptake-proteins on Cell1? are reuptake-proteins the same as receptor-proteins on Cell2?
 
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Mastemah

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To quote an old argument for thought, why arent there receptors being discovered for old things that wrk? Where is the aspirin receptor?
 

Kyle M

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But haven't they been separately identified /isolated and sequenced ?
Incomplete I can understand but bunk - could you elaborate your experience ?
For example blocking the so called AR (androgen receptor) or AR antagonist stops MPB .

Diokine explained it pretty well a few posts above.

Do AR antagonists stop MPB in all patients that try it? Conversely, do all MPB sufferers have higher AR signaling, and do all non-MPB sufferers have lower AR signaling? If not, how can AR signaling be the cause of MPB?
 

Travis

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Gilbert Ling used the term "cardinal adsorbant" for ATP. Where this molecule docks (a lysine IIRC) is called a receptor. Gilbert ling wasn't against the concept of the receptor.

I personally believe there is nothing wrong with receptors if they can be proven. They are necessary at times. The problem is is that some receptors are simply assumed to be there. Ray Peat's article, if I remember correctly, pointed out other ways that molecules can influence biology.

Colligative properties like structuring water, or changing hydrophobicity nonspecifically everywhere on the cell layer. Just because a molecule influences biology does not necessarily mean it does so by bonding to a protein "receptor".

I believe Harold Hillman pointed out that the amount of receptors thought to occupy a cell membrane can exceed the surface area of said membrane. The idea that they 'project' from the surface is most likely false.

It can result in the same type of circular logic as enzyme nomenclature, since it is defined by an activity and a substrate. If you know that the drug you are studying gets stereospecifically hydroxylated at carbon #4 on the indole ring and a cell culture can be shown to have 4α-indole hydroxylase activity, you could propose an enyme called 4α-indole hydroxylase or some such thing. They turn an activity into a noun, and the noun is always presumed to be a protein.

I think Ray Peat would sees this as a leap of faith in some cases.

And receptors are named in a similar fashion, by their substrate.

There is good evidence that small molecules do specifically interact with proteins however. There are thousands of cases that have been adequately proven.

In this image of T₃-deiodinase (inactivates thyroid hormone), you can see stick models of molecular structures overlaid on generic enzyme model (the familiar helix and sheet type modeling) next to an experimentally determined electron density map (D).

F2.large.jpg


T₃ can be seen in yellow. This shouldn't be though of as absolute; more like a freeze-frame. Each σ-bond can freely rotate to find it's lowest energy state.

The selenocysteine is thought to play the largest role here, reducing the iodine atom causing to be eliminated. A proton is thought to replace the iodine from the back, donated by His²¹⁹ (not shown). It kinda looks like the T₃ molecule was placed in there as an afterthought. I think it could be done better.

Crystal structure of mammalian selenocysteine-dependent iodothyronine deiodinase suggests a peroxiredoxin-like catalytic mechanism

They use x-ray crystallography to create an electron density map and used this information, along with the protein's sequence, to model the 3-dimensional shape of the protein. They then try to figure out how well the molecule fits in the purported catalytic site or receptor based on chemical laws of attraction. For instance, carboxyl (glu, asp) groups carry a full negative change at physiological pH and amino (–NH₃⁺, lys) groups a full positive charge. Together, these can interact strongly with the substrate if the substrate has a suitable conjugate charge distribution. There are also hydrogen bonds and hydrophobic factors to consider.

But cheap and lazy cartoons in some biology books have been known to simply model this interaction as a small triangle filling in the triangular void of a square, a lock and key, or some other insulting nonsense.

I think even with an electron density map created from x-ray crystallography, there can still be much wishful thinking involved. There is good reason to think that the shape the protein takes in solvent (water) is different than the shape it takes when dry and crystallized. Moreover, catalytic sites and receptors can be located inside a protein that 'unfurls' as a response to pH, ATP, or some 'cardinal adsorbant'.

Receptor affinities can be measured kinetically. If a protein bonds, to estradiol for instance, at an affinity of 1.1(10⁶), anything that displaces it could be considered to have a higher binding affinity for the so-called 'estrogen receptor'. Affinities are defined as the change in Gibbs free energy which can be calculated from the enthalpy of interaction (and entropy). The enthalpy can be determined of one has access to a calorimeter. These receptor-ligand interactions give of a small, but measurable, amount of heat. The stronger the binding, the more heat is liberated.

So even with the the best orthodox science there is some degree of uncertainty about receptors, especially the ones that aren't even x-rayed and sequenced.

I think you have to take it on a case-by-case basis and read the studies on each 'receptor' to determine it's ontological status.
 
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L

lollipop

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Gilbert Ling used the term "cardinal adsorbant" for ATP. Where this molecule docks (a lysine IIRC) is called a receptor. Gilbert ling wasn't against the concept of the receptor.

I personally believe there is nothing wrong with receptors if they can be proven. They are necessary at times. The problem is is that some receptors are simply assumed to be there. Ray Peat's article, if I remember correctly, pointed out other ways that molecules can influence biology.

Colligative properties like structuring water, or changing hydrophobicity nonspecifically everywhere on the cell layer. Just because a molecule influences biology does not necessarily mean it does so by bonding to a protein "receptor".

I believe Harold Hillman pointed out that the amount of receptors thought to occupy a cell membrane can exceed the surface area of said membrane. The idea that they 'project' from the surface is most likely false.

It can result in the same type of circular logic as enzyme nomenclature, since it is defined by an activity and a substrate. If you know that the drug you are studying gets stereospecifically hydroxylated at carbon #4 on the indole ring and a cell culture can be shown to have 4α-indole hydroxylase activity, you could propose an enyme called 4α-indole hydroxylase or some such thing. They turn an activity into a noun, and the noun is always presumed to be a protein.

I think Ray Peat would sees this as a leap of faith in some cases.

And receptors are named in a similar fashion, by their substrate.

There is good evidence that small molecules do specifically interact with proteins however. There are thousands of cases that have been adequately proven.

In this image of T₃-deiodinase (inactivates thyroid hormone), you can see stick models of molecular structures overlaid on generic enzyme model (the familiar helix and sheet type modeling) next to an experimentally determined electron density map (D).

F2.large.jpg


T₃ can be seen in yellow. This shouldn't be though of as absolute; more like a freeze-frame. Each σ-bond can freely rotate to find it's lowest energy state.

The selenocysteine is thought to play the largest role here, reducing the iodine atom causing to be eliminated. A proton is thought to replace the iodine from the back, donated by His²¹⁹ (not shown). It kinda looks like the T₃ molecule was placed in there as an afterthought. I think it could be done better.

Crystal structure of mammalian selenocysteine-dependent iodothyronine deiodinase suggests a peroxiredoxin-like catalytic mechanism

They use x-ray crystallography to create an electron density map and used this information, along with the protein's sequence, to model the 3-dimensional shape of the protein. They then try to figure out how well the molecule fits in the purported catalytic site or receptor based on chemical laws of attraction. For instance, carboxyl (glu, asp) groups carry a full negative change at physiological pH and amino (–NH₃⁺, lys) groups a full positive charge. Together, these can interact strongly with the substrate if the substrate has a suitable conjugate charge distribution. There are also hydrogen bonds and hydrophobic factors to consider.

But cheap and lazy cartoons in some biology books have been known to simply model this interaction as a small triangle filling in the triangular void of a square, a lock and key, or some other insulting nonsense.

I think even with an electron density map created from x-ray crystallography, there can still be much wishful thinking involved. There is good reason to think that the shape the protein takes in solvent (water) is different than the shape it takes when dry and crystallized. Moreover, catalytic sites and receptors can be located inside a protein that 'unfurls' as a response to pH, ATP, or some 'cardinal adsorbant'.

Receptor affinities can be measured kinetically. If a protein bonds, to estradiol for instance, at an affinity of 1.1(10⁶), anything that displaces it could be considered to have a higher binding affinity for the so-called 'estrogen receptor'. Affinities are defined as the change in Gibbs free energy which can be calculated from the enthalpy of interaction (and entropy). The enthalpy can be determined of one has access to a calorimeter. These receptor-ligand interactions give of a small, but measurable, amount of heat. The stronger the binding, the more heat is liberated.

So even with the the best orthodox science there is some degree of uncertainty about receptors, especially the ones that aren't even x-rayed and sequenced.

I think you have to take it on a case-by-case basis and read the studies on each 'receptor' to determine it's ontological status.
@Travis I appreciate the time you took to answer this question. I had the same question and between Diokine's answer and yours here, I had a much better grasp of the subject. Feeling grateful.
 

Travis

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Here you can find a seven page rant by Ray Peat about estrogen receptors: Estrogen Receptors — what do they explain?

As early as 1971, Ray Peat speculated that estrogen receptors didn't actually exist in the way they were thought to. He provides good logic and an entertaining narrative to support this.

The idea that a molecule or an atom could work in other ways was advanced by Linus Pauling in the early 60s and was necessary to explain one odd finding: noble gasses such as xenon produced anesthesia.

Noble gasses don't bind to anything at all, not even water. They are chemically inert. Other nonpolar small molecules produce anesthesia like chloroform and argon. They were found to produce anesthesia in proportion to the degree that they disrupt the water lattice. What these small apolar atoms (or molecules) do is displace water into a pentagonal docedahedrons with the gas molecule in the center.

pauling.png
pauling3.png

From the original Pauling article that can be found here.

The reordering of the water affects the movements of ions through it. This, according to Pauling, is why electrical waves decrease in amplitude under anesthesia. General anesthetics decrease brain current by increasing impedence to electrical flow in the brain's water, a more ordered array of water that resists ionic mobility.

The structuring power of certain small nonpolar molecules can be demonstrated by dissolving tetrabutylammniumhydroxide in water. This raises the melting point of water to 30°C (86°F). (MSDS and Horizons in Biochemistry [p537])

So even at constant body temperature, some molecules decrease the entropy of water towards a more ordered or 'frozen' state. This can affect the electrical properties.

The concept has been shown visually in the lab. Researchers used fluorescent water, a microscope, and tiny beads to visualize the structured water in the presence and in the absence of lidocaine:
structured water.png

The micropshere exclusion zone is an area of more highly structured water.

They showed that increased concentrations of lidocaine increased the size of the exclusion zone, another case of an anesthetic structuring water. Effect of Local and General Anesthetics on Interfacial Water

Yet you can find publications by people proposing a chloroform protein receptor, a lidocaine receptor, and even an argon receptor. No ***t. Here is a quote:

The biological activity of argon can be attributed to its atomic structure interactions with enzymes and receptors. Though argon is unable to form strong covalent bonds to produce chemical reactions, it does have the capacity to interact with enzymes and receptors through charge-induced dipole and van der Waals interactions as a stabilizing component key in relating argon’s ability as an anesthetic and neuroprotectant.

Face palm. The weakest possible intermolecular forces are invoke to explain this.

He doesn't actually explain anything. Rubbing against a 'GABA receptor' doesn't explain anything. Water itself can form van der Waals interactions with the 'GABA receptor', charge-induced dipoles, and hydrogen bonds. The article has 78 references and doesn't mention Linus Pauling even once.

Argon gas: a potential neuroprotectant and promising medical therapy
 

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Christoph

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The receptor doctrine presupposes that cells have impermeable membranes. To interact with their environment, cells require the intellectual fabrications of pumps, channels and receptors. Receptors are proteins embedded in the impermeable cell wall. Specific compounds physically attach to specific receptors, who then diligently transmit signals to the interior of the cell where machine-like mechanisms are invoked. Gilbert Ling, Harold Hilman, Ray Peat and others argued against this doctrine. In one account, Ray likens the receptor doctrine to 6th-grade-level-propaganda. He argues that the drug industry created and sustained the receptor doctrine primarily for marketing purposes:

Serotonin: Effects in disease, aging and inflammation

In another of Ray's articles, he refers to Vernadski's metaphor, that an organism is a whirlwind of atoms:

Fats, functions and malfunctions.

Which now brings us to Gerald Pollack. His research into water and how it's applied to cellular biology is compelling and overwhelming. In Pollack's model, cell walls are permeable meshes of protein and fat. The interior of the cell has both liquid water and gelatinous water (4th phase of water or EZ water). Any and all chemicals that come in contact with a cell may interact with it. In Pollack's/Peat's view of the organism, it is a whirlwind of chemical reactions.

https://www.amazon.com/Fourth-Phase-Water-Beyond-Liquid/dp/0962689548
Cells, Gels and the Engines of Life: Gerald H. Pollack: 9780962689529: Amazon.com: Books

When Ray uses the term receptor, I assume he actually means it within quotes, "receptor" and, I understand it to mean a "biochemical effect." It's a term of convenience.
 

Travis

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I feel as though I have to defend the idea of the receptor. Enzymes show that small molecules interacts specifically with proteins. Many chemical metabolites formed within the body are exclusively chiral, meaning only one mirror image variety is found:
enantiomer1.png

Also, many drugs are chiral. Many drugs have only one active stereoisomer:
Levorotary–isomer of all β-blockers is more potent in blocking β-adrenoceptors than their dextrorotary-isomer, such as S(-)-propranolol is 100 times more active than its R(+)-antipod.
Chiral Drugs: An Overview

And molecules like ATP and acetocholine must interact with proteins somehow otherwise there would be no muscle contraction.

I think the concept of the receptor is important but should be used carefully. There could be many drugs which work in other ways. Linus Pauling proved that most general anesthetics don't work through a protein receptor but work by structuring water and Ray Peat made a good case against the estrogen receptor.





 

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