Androgen receptors in the brain: what are we measuring?

Science
#1

It’s no wonder we get hit with mental symptoms we have 3 categories of AR receptors in the brain. This is troubling. Dht in the brain acts on the central nervous system. So after reading this I assume we don’t have brain damage yet but rather AR receptors not functioning properly. What the long term consequences of this I don’t know.

It is proposed that there are three categories of receptors for androgen in the brain. One receptor preferentially binds testosterone and a second one preferentially binds DHT. Both of these receptors are in equilibrium between nucleus and cytoplasm according to the free water content of the compartments. Both of these receptors can be activated and transformed by steroid and thus concentrate in the nucleus. It is proposed that a third receptor binds both steroids with the same relative affinity. However, this third receptor can only be activated but not transformed (i.e. it does not concentrate in the nucleus). The proposed system implies that testosterone acts on a few discrete populations of neurons in the brain while DHT has a very diffuse action on the central nervous system.

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#2

That study is from the early 80’s and I wonder if they weren’t observing different localizations of the primary AR and describing it as different types.

Some more information here about a transmembrane receptor for androgens encoded by a different gene than “the” AR:

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#3

Don’t AR receptors shed themselves and regrow yet when they come back they continue in this over sensitive state. So directly altering the sensitivity wont work. If we had fewer receptors would that help? I think less receptors even more sensitivity. Or is a mechanism keeping the receptors in this state regardless. I feel overwhelmed at the thought of trying to fix this.

#4

They don’t really shed, so much as become degraded and replaced:

D. K. Lee and C. Chang, “Expression and Degradation of Androgen Receptor: Mechanism and Clinical Implication,” J Clin Endocrinol Metab , vol. 88, no. 9, pp. 4043–4054, Sep. 2003.

The life cycle of AR is followed in the above article, from transcription of AR mRNA, to degradation by proteosomes. Degradation of misfolded/denatured proteins is also touched-upon. There are also estimated half-lives of AR provided that are hours, not days, months, or years.

There are many other proteins that interact with them to give them their “sensitivity.”

Yeah, it’s overwhelming to even learn enough about this stuff to begin to understand it.

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#5

So the way I’m reading it is that a protein is making the receptors sensitive. However there is a drug that can lower the sensitivity of the receptor. Somebody here tried that drug for a short while and it never worked. Admin are aware of this drug but obviously don’t think it’s the cure otherwise they’d have tried it. Which leaves me further confused. Sensitivity is the apparent issue.

Taken from the link

The CpG island of the AR gene is heavily methylated in androgen-independent human prostate cancer DU145 cells, resulting in masked AR expression (85, 87, 88). Treatment of the demethylation reagent 5-aza-2′-deoxycytidine restored AR expression in DU145 cells (87).

Sorry @Dubya_B am I reading this right. The heavy methylation caused AR expression or hid the AR expression. This AR expression was then fixed by lowering the methylation with 5 aza. And in DU145 cells we have AR receptors.

#6

That was in the DU145 cell line and it appears to continue growing/dividing even without significant expression of AR.

This isn’t necessarily the same problem as in PFS patients. We just don’t know exactly what’s going on yet, but an over-expression of AR was found in penile tissue of PFS patients.

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#7

We don’t know if some of the affected AR are in the cells that 5 aza demethylates. So far Crispr looks the most specific demethylation treatment in research studies.

#8

Thanks for your insight @Dubya_B

#9

So because of the above reasons do you think theres no way this would work or just there’s reasons why it may not work.

#10

I think CRISPR “could” work. It all falls on us finding what exactly causes this condition in us.

The demethylating agents are often used in lethal concentrations in studies done on colonies of cells in a petri dish. Also, 5-aza passively demethylates during cell division, meaning it wouldn’t work on many cells in the nervous system.

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