Niacinamide Binds And Activates GPc Estrogen Receptor

[LeeLemonoil]

The GPER is defined as an "estrogen receptor" Unlike ERa and ERß, it is not a nuclear receptor. It is theorized that GPER is involved in or the reason of rapid cellular effects of estrogens.

This publication http://www.sciencedirect.com/science/article/pii/S0039128X16000544
gives some insight into its actions and states some known agonists and antagonists.

Curiously, Niacinamide is an agonist. Other agonists are Xenoestrogens and poisons like BPA, Green Tea Cathechins and other Flavanoids. Tamoxifen, a known anti-estrogenic pharmacon, is also an agonist.

The understanding of the actions of GPER is crucial to Ray Peat's theses.

As far as I'm aware, he always said tha Estrogens act rapidly and independently from estrogen receptor activation. This GPER (a protein structure in cells for all intents and purposes, no need to all it receptor really) does confirm this idea.

 

[Drareg]

The GPER is defined as an "estrogen receptor" Unlike ERa and ERß, it is not a nuclear receptor. It is theorized that GPER is involved in or the reason of rapid cellular effects of estrogens.

This publication http://www.sciencedirect.com/science/article/pii/S0039128X16000544
gives some insight into its actions and states some known agonists and antagonists.

Curiously, Niacinamide is an agonist. Other agonists are Xenoestrogens and poisons like BPA, Green Tea Cathechins and other Flavanoids. Tamoxifen, a known anti-estrogenic pharmacon, is also an agonist.

The understanding of the actions of GPER is crucial to Ray Peat's theses.

As far as I'm aware, he always said tha Estrogens act rapidly and independently from estrogen receptor activation. This GPER (a protein structure in cells for all intents and purposes, no need to all it receptor really) does confirm this idea.

I only had a quick look but is the study not referring to niacin and not niacinamide?

 

[LeeLemonoil]

No, both, as referenced under 76.

 

[haidut]

The GPER is defined as an "estrogen receptor" Unlike ERa and ERß, it is not a nuclear receptor. It is theorized that GPER is involved in or the reason of rapid cellular effects of estrogens.

This publication http://www.sciencedirect.com/science/article/pii/S0039128X16000544
gives some insight into its actions and states some known agonists and antagonists.

Curiously, Niacinamide is an agonist. Other agonists are Xenoestrogens and poisons like BPA, Green Tea Cathechins and other Flavanoids. Tamoxifen, a known anti-estrogenic pharmacon, is also an agonist.

The understanding of the actions of GPER is crucial to Ray Peat's theses.

As far as I'm aware, he always said tha Estrogens act rapidly and independently from estrogen receptor activation. This GPER (a protein structure in cells for all intents and purposes, no need to all it receptor really) does confirm this idea.

It is also an antagonist of the classical ER by inhibiting SIRT.
Niacinamide Is Anti-estrogenic

The study [76] also says niacinamide is highly beneficial for melanoma and that the role of the GPER protein is not well known as it is capable of binding all kinds of stuff include estrogen antagonists.

 

[Dante]

No, it did not. Where the hell did you see that statement?!??
Here is the only place that I see discussing nicotinamide / niacinamide.
"...A recent study found that nicotinamide, the amide form of niacin, inhibits vasculogenic mimicry in vitro [134], a pathway that has been implicated in the pathogenesis of highly aggressive melanoma. An inhibitor effect on vasculogenesis would be compatible with GPER activation [10]. Also, a dramatic beneficial effect of niacin on UV-induced DNA damage in patients with autosomal recessive xeroderma pigmentosum (Cockayne syndrome) has been recently reported, which possibly involves GPER activation."

So, an effect "compatible with GPER activation" to you means niacinamide is an estrogen agonist? Please show me the studies discussing binding kinetics of niacinamide to that GPER and EC50 for niacinamide.

Can't it be an "inverse agonist"?

 

[ReSTART]

What is "reverse translational medicine"? Ctrl+f in the article if you don't know what I'm talking about.

 

[haidut]

Can't it be an "inverse agonist"?

Possibly. The reference [76] does talk about niacin and niacinamide being agonists but it also talks about their "unexpected" beneficial effects. So, it could be inverse agonism at play.

 

[LeeLemonoil]

I'm not suggesting that NAM is an estrogenic substance. To the contrary, these studies will clarify:

From "76": Niacin activates the G protein estrogen receptor (GPER)-mediated signalling. - PubMed - NCBI
Together, our findings concerning the agonist activity for GPER displayed by both nicotinic acid and nicotinamide broaden the mechanisms involved in the biological action of these molecules and further support the potential of a ligand to induce different responses mediated in a promiscuous manner by distinct GPCRs.

In the subject researched in that article, Niacinamide is clearly beneficial and is therefore a favourable ligand.
Reminds me of ß-diol at the ERß for example, no @Dante ?
It binds on a "receptor" that Estrogens can also bind to, but elicits positive effects - so, it's even more than just "blocking".

This study will make it even more clear:
https://elifesciences.org/content/5/e15104

Scientists have discovered that Estrogens that activate GPER induce skin-tanning, while activation of "progestin and adipoQ receptor 7 (PAQR7)" (activated by Progesteron!) prevents that increase in melanin-genesis (reciprocally regulate melanin synthesis).
The scientist even acknwoledge that, among others, melanin-increase mediated by GPER is among others induced also by inflammatory cytokines. Regardless, they are researching now synthetic estrogen derivates that activate GPER but not the classical ERs for skin-tanning products. Oh my, we all know how "safe" they will, epspecially when Progesterone is naturally a regulatory substance.
Niacinamide also has well known skin-lightening effects and offers UV-Protection. Another indication that Niacinamides binding to GPER has opposite effects to Estrogens when binding to GPER.

Also to be kept in mind when considering this: as I've posted in my ß-Ionone threads, ß-Ionone bind to another G-protein couple Receptor in melanocytes and can increase melanin-genesis, and DHT binds to that receptor as well, at least in the prostate. So maybe and very possibly, Androgens play apart in melanin-genesis as well and are probably the saner solution than estrogen based derivates

 

[haidut]

I'm not suggesting that NAM is an estrogenic substance. To the contrary, these studies will clarify:

From "76": Niacin activates the G protein estrogen receptor (GPER)-mediated signalling. - PubMed - NCBI
Together, our findings concerning the agonist activity for GPER displayed by both nicotinic acid and nicotinamide broaden the mechanisms involved in the biological action of these molecules and further support the potential of a ligand to induce different responses mediated in a promiscuous manner by distinct GPCRs.

In the subject researched in that article, Niacinamide is clearly beneficial and is therefore a favourable ligand.
Reminds me of ß-diol at the ERß for example, no @Dante ?
It binds on a "receptor" that Estrogens can also bind to, but elicits positive effects - so, it's even more than just "blocking".

This study will make it even more clear:
https://elifesciences.org/content/5/e15104

Scientists have discovered that Estrogens that activate GPER induce skin-tanning, while activation of "progestin and adipoQ receptor 7 (PAQR7)" (activated by Progesteron!) prevents that increase in melanin-genesis (reciprocally regulate melanin synthesis).
The scientist even acknwoledge that, among others, melanin-increase mediated by GPER is among others induced also by inflammatory cytokines. Regardless, they are researching now synthetic estrogen derivates that activate GPER but not the classical ERs for skin-tanning products. Oh my, we all know how "safe" they will, epspecially when Progesterone is naturally a regulatory substance.
Niacinamide also has well known skin-lightening effects and offers UV-Protection. Another indication that Niacinamides binding to GPER has opposite effects to Estrogens when binding to GPER.

Also to be kept in mind when considering this: as I've posted in my ß-Ionone threads, ß-Ionone bind to another G-protein couple Receptor in melanocytes and can increase melanin-genesis, and DHT binds to that receptor as well, at least in the prostate. So maybe and very possibly, Androgens play apart in melanin-genesis as well and are probably the saner solution than estrogen based derivates

Yep, I spoke too soon in that first post of mine, which I subsequently edited but somebody already quoted me so it was too late
Maybe the name GPER is a bad name. It is a receptor that many substances bind to and exert rapid, non-genomic effects and one of them is estrogen. I have not done much research on GPER. Do you know why it is called that way? Maybe the first person to study it was using estrogen and this is why the name stuck.

 

[LeeLemonoil]

Maybe the first person to study it was using estrogen and this is why the name stuck.

I'd guess so, but don't know either. I knew the thread-title would cause a stir ... But technically it says the truth because of the misleading name.

Pls look into the provided study on skin-tanning/melanin-genesis. These G-coupled receptor structures are seemingly involved in many effects of steroids.
I'm really not well-versed in RP's theorem, but I think research into them and action of steroids on them will prove him right on many things. He describes actions of steroids independently from the classical ERs and AR does'nt he? If mainstream science needs to classify the many protein structures and cell sites whre steroids act as Recepto suprafamilies, so be it. There is a good paragraph in the overview I posted in the first link, that describes how GPER action is highly interlinked with many other Receptors - this is what it is all about, and many of the mechanisms involved wil be in line with what RP anticipated

 

[haidut]

I'd guess so, but don't know either. I knew the thread-title would cause a stir ... But technically it says the truth because of the misleading name.

Pls look into the provided study on skin-tanning/melanin-genesis. These G-coupled receptor structures are seemingly involved in many effects of steroids.
I'm really not well-versed in RP's theorem, but I think research into them and action of steroids on them will prove him right on many things. He describes actions of steroids independently from the classical ERs and AR does'nt he? If mainstream science needs to classify the many protein structures and cell sites whre steroids act as Recepto suprafamilies, so be it. There is a good paragraph in the overview I posted in the first link, that describes how GPER action is highly interlinked with many other Receptors - this is what it is all about, and many of the mechanisms involved wil be in line with what RP anticipated

I will look into it. I already posted a study on the opposing effects of estrogen and progesterone on skin tan.
Estrogen Darkens Skin Color, Progesterone Lightens It

I think the main effects that Peat focuses on in terms of explaining the activity of any substance has to do with its electronic properties - i.e. is it an oxidizing or reducing agent. Progesterone happens to be a strong oxidizing one, but unlike the quinones that Koch worked with, it seems to have very low toxicity and somehow prevents oxidative stress even when taken in very high doses.

 

[Kyle M]

The lab I was just in worked on this "receptor." We had a transgenic, knock-in knock-out mouse strain that preserved the supposed membrane receptor activity without the nuclear receptor activity. Long story short, I don't really buy the whole thing.

 

[LeeLemonoil]

@Kyle M
thanks, interesting info. What exactly do you not buy/made you think so if you don't mind elaborating a bit? Don't believe there is an independent GPER activity?

@haidut
I see now that you already posted and commented the dermatologic study I refered to already in another, older thread. Good info there.

 

[Dante]

The lab I was just in worked on this "receptor." We had a transgenic, knock-in knock-out mouse strain that preserved the supposed membrane receptor activity without the nuclear receptor activity. Long story short, I don't really buy the whole thing.

So, same doubt as above . Does the protein (receptor) not exist according to you or the -" transgenic, knock-in knock-out mouse strain that preserved the supposed membrane receptor activity without the nuclear receptor activity" can't happen ?

 

[bdawg]

would niacinamide theoretically produce a similar effect through activating GPER as below?

Activation of GPER-1 Estradiol Receptor Downregulates Production of Testosterone in Isolated Rat Leydig Cells and Adult Human Testis

 

[LeeLemonoil]

would niacinamide theoretically produce a similar effect through activating GPER as below?

Activation of GPER-1 Estradiol Receptor Downregulates Production of Testosterone in Isolated Rat Leydig Cells and Adult Human Testis

No, it would likely, from all I gather from the studies and findings discussed in this thread, prevent E2's effects.

 

[LeeLemonoil]

Another study on GPER. Hydroxytyrosol and Oleuropin counteract 17ß-Estradiols (E2) proliferation effects in breast cancer cells.
They call them "inverse agonist". That's waht Niacinamide is as well.

HyTyrosol and OLEU are phenols from Olive leaf and Olive oil.

Oleuropein and hydroxytyrosol activate GPER/ GPR30-dependent pathways leading to apoptosis of ER-negative SKBR3 breast cancer cells. - PubMed - NCBI

Oleuropein does rais Test and lower Cortisol in rats:
http://www.jnutbio.com/article/S0955-2863(12)00158-1/abstract

 

[Kyle M]

@Kyle M
thanks, interesting info. What exactly do you not buy/made you think so if you don't mind elaborating a bit? Don't believe there is an independent GPER activity?

I think that the estrogen receptor is simply a protein that holds estrogen in the cell, and that the whole cell can respond to estrogen. This is pretty clear from the triple ER negative tumor cells that still have a strong growth response from estrogen. The difference with them is that an ER blocker does not help, like it does with ER positive tumor cells. This suggests to me that knocking back the cell's ability to hold estrogen (by binding with a "receptor") knocks down estrogenic activity in the cell; this is obviously not possible when there is no receptor to oppose. In that case, transitory estrogen moves in and out of the cell and does its work.

I believe that the protein exists, and that it mediates estrogen activity in the cell as I described above, but that the classical receptor theory and the rapid activity membrane receptor activity theory are attributing the measurable actions to a fictional mechanism.

One of the first red flags I found in this field was that my advisor, who did a post doc in one of the labs that discovered the GPER, couldn't explain the idea very well to me. I had a few technical questions to help me understand what he was saying, and he basically kept repeating the canned explanation of the receptor and its various domains. He was currently running a lab in an R1 institution with a large grant based on his work in this area. I'm sure you can imagine how this affected my confidence in the theory. When I started reading Ray Peat's explanations of estrogen it sealed the deal for me, he clearly understands what he's talking about at least, these other people can hardly reproduce the textbook theory without tripping up on the words, let alone expand into a satisfying explanation for an inquisitive graduate student.

P.S. - here's a study I grabbed quickly that shows estrogen action in ER-negative cells: Estradiol increases ER-negative breast cancer metastasis in an experimental model

 

[Such_Saturation]

One of the first red flags I found in this field was that my advisor, who did a post doc in one of the labs that discovered the GPER, couldn't explain the idea very well to me. I had a few technical questions to help me understand what he was saying, and he basically kept repeating the canned explanation of the receptor and its various domains. He was currently running a lab in an R1 institution with a large grant based on his work in this area.

 

[haidut]

I think that the estrogen receptor is simply a protein that holds estrogen in the cell, and that the whole cell can respond to estrogen. This is pretty clear from the triple ER negative tumor cells that still have a strong growth response from estrogen. The difference with them is that an ER blocker does not help, like it does with ER positive tumor cells. This suggests to me that knocking back the cell's ability to hold estrogen (by binding with a "receptor") knocks down estrogenic activity in the cell; this is obviously not possible when there is no receptor to oppose. In that case, transitory estrogen moves in and out of the cell and does its work.

I believe that the protein exists, and that it mediates estrogen activity in the cell as I described above, but that the classical receptor theory and the rapid activity membrane receptor activity theory are attributing the measurable actions to a fictional mechanism.

One of the first red flags I found in this field was that my advisor, who did a post doc in one of the labs that discovered the GPER, couldn't explain the idea very well to me. I had a few technical questions to help me understand what he was saying, and he basically kept repeating the canned explanation of the receptor and its various domains. He was currently running a lab in an R1 institution with a large grant based on his work in this area. I'm sure you can imagine how this affected my confidence in the theory. When I started reading Ray Peat's explanations of estrogen it sealed the deal for me, he clearly understands what he's talking about at least, these other people can hardly reproduce the textbook theory without tripping up on the words, let alone expand into a satisfying explanation for an inquisitive graduate student.

P.S. - here's a study I grabbed quickly that shows estrogen action in ER-negative cells: Estradiol increases ER-negative breast cancer metastasis in an experimental model

Triple negative breast cancer still responds to progesterone and estrogen (as the study you found point out). So, the receptor is not always needed to allow a steroid to affect a cell. Since estrogen, just like PUFA, makes the cell more hydrophillic, which allows it to uptake more estrogen you can reduce a cell's response to estrogen by simply making it more lipophillic. Things like tocopherol, SFA, sodium, magnesium, CO2, certain steroids, etc all can change the cell's affinity for water and thus oppose estrogen's entrance and effects even in the absence of a receptor.