CRH-CRHR1 mutation

[trainman04]

adenylate cyclase is an enzyme with key regulatory roles in essentially all cells.

DNA > mRNA > Protein(CRH cells)

I did a search on SelfDeCode and it turns out I have 6 mutations for regulating Protein expression...

https://www.selfdecode.com/gene/mc4r/
''The mutant version of the MC4R gene produces a protein receptor that doesn't activate as well - it is less sensitive to signals from the body that tell the body that it is already full.''

https://www.selfdecode.com/gene/mtnr1b/
''The activity of this receptor is mediated by pertussis toxin sensitive G proteins that inhibit adenylate cyclase activity.''

https://www.selfdecode.com/gene/chrm3/
''It also inhibits adenylate cyclase''

https://www.selfdecode.com/gene/gabbr2/
''Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase.''

https://www.selfdecode.com/gene/adrb1/
''Beta-adrenergic receptors mediate the catecholamine-induced activation of adenylate cyclase through the action of G proteins. ''

https://www.selfdecode.com/gene/fshr/
''The activity of this receptor is mediated by G proteins which activate adenylate cyclase.''

So this means due to all these mutations stacking up the adenylate cyclase which is supposed to regulate CRH is not being regulated.

I also have a mutation in my CRHR1 but not CRH or CRHR2. But CRHR1 can only be activated Via CRH right? So what would be causing high CRH to go trough CRHR1? Is it possible that due to the mutations not regulating the CRH protein cells and it somehow overactives CRHR1 which slowly made me more susceptible/prone to stress and the anxiety effect built up ? Is it possible due to the mutation in CRHR1 demands more CRH to be made? No idea or do I have a gene duplication in CRH/CRHR1?.. (doubt it)
I don't think I have a CRH-Secreting tumor either well atleast not in the brain tissues cause I did a brain scan but not full body anyhow outside of brain tissue it wouldn't affect me anyway.

Here are my CRHR1 mutations but I have no idea what they mean:

https://www.selfdecode.com/gene/crhr1/
https://www.selfdecode.com/gene/crhr1-it1/ (gene duplication?) <-? Intronic RNAs constitute the major fraction of the non-coding RNA in mammalian cells)
https://www.selfdecode.com/gene/mgc57346-crhr1/ (gene duplication?) <-? ADP-ribosylation factor)

can someone explain what the last two CRHR1 are?

Hm.....So I doubt I have gene duplication either , and no tumors either, and I don't think my body is making excess CRH mRNA. It is just my body is not enzyme (adenylate cyclase) is not regulating CRH protein expression..

it is possible to have low mRNA but high protein expression becuase a single mRNA molecule can stick around and be translated many times (which mine is becuase the enzyme is not regulating it!!!!!!!!)

Consider an enzyme: An mRNA molecule is translated to make a protein, which has enzymatic activity on some substrate, and can be regulated.

Expression is a readout for the translation of the mRNA into stable protein.

constitutive protein activity - "Constitutive" activity means that the regulation of the enzyme's activity is gone, it's been mutated or something to allow it to always be active.

So the text in Bold I believe is the issue, Are there any other things Im forgetting besides adenylate cyclase?
Becuase my DNA is fine then > mRNA is fine then when it is about to become protein the adenylate cyclase enzymes has to be active and able to regulate how much is becoming CRH protein...Now once it is an CRH protein I think the adenylate cyclase still can regulate it but the multiple mutation stacks are too many and the CRH becomes excess and now the CRHR1 mutations play a role and gets overactivated.


the questions:
1. Im just wondering is this possible could this be happening?
2. Its not possible for CRHR1 receptors to be activated any other way other than with its ligand CRH right? so no mutations that feed protein or something trough an loophole directly bypassing CRH?

 

[sekio]

So this means due to all these mutations stacking up the adenylate cyclase

Which adenylate cyclase? And where? Adenate cyclases are a whole family of protiens regulated by a whole bunch of stuff. And I'm pretty sure cAMP hydrolyses by itself at physiological pH eventually anyway.

a single mRNA molecule can stick around and be translated many times (which mine is becuase the enzyme is not regulating it!!!!!!!!)

Well, yeah, but eventually other cellular RNases will shred the thing, and statistically speaking it only has a 2/3 probability of ever returning to the receptor, assuming random Brownian motion in 3 axes. So overall mRNA will always have a limited lifetime.

You should spend a while tracking down and reading Molecular Biology Of The Cell... this is another case of "knowing just enough to be overconfident"...

 

[trainman04]

Which adenylate cyclase? And where? Adenate cyclases are a whole family of protiens regulated by a whole bunch of stuff. And I'm pretty sure cAMP hydrolyses by itself at physiological pH eventually anyway.

whichever enzyme regulates CRH . What enzyme regulates CRH once it has become a protein?

CRHR1 can only be activated via CRH right? so inhibit CRH in the PVN first less CRHR1 and CRH circulating in the brain? (I just wanna make sure there is no other way for CRHR1 to be activated ie mutations)

But I think my ''rat'' has high circulating CRH protein expression for some reason. do you think giving him Clomipramine which has been shown to reduce CRH mRNA in PVN will help him? or do I need to give him something that inhibits CRH like valproate (reduce CRH in PVN) or Carbamazepine (inhibit hypothalmic CRH)?

I saw a study it said: ''Moreover, CRF mRNA expression was decreased in the central nucleus of the amygdala (CeA) and paraventricular nucleus (PVN) of the hypothalamus''

how is it possible for there to be CRF mRNA expression in the amygdala? I thought DNA > mRNA > Protein (CRH) was created in the PVN of the hypothalamus First then sent trough the whole brain system to other places. So can the amygdala and other places etc create their own CRH with mRNA/DNA etc?

also what does '' results in decreased expression of CRHR1 mRNA.''
I thought CRHR1 were receptors? not something that is made with mRNA? and that CRHR1 is activated by CRH.

 

[Limpet_Chicken]

Receptors are proteins Trainman, they, like the rest of our bodily constituents come to be by virtue of mRNA (unless you count the DNA that RNA transcripts are created from).

But anyhow, receptors of any kind are just proteins which behave in specific ways when a ligand binds, be it changing conformation, on a more simple level, from an ion channel (composed of protein subunits) being closed in it's resting state, and when bound by an (agonist) ligand, changes it's 3D shape to allow passage of ion flux currents, to complex arrangements of interacting, but separate proteins, such as a receptor protein associating with a G-protein, which when the receptor is activated, binding and hydrolyzing guanosine triphosphate (when bound to GTP a G-protein is active, when bound to the diphosphate, they are in a quiescent state), and through the G-protein, multiple intracellular cascades of chemical messengers can be activated, which in turn, modulate gene transcription in the appropriate way.

 

[trainman04]

Receptors are proteins Trainman, they, like the rest of our bodily constituents come to be by virtue of mRNA (unless you count the DNA that RNA transcripts are created from).

But anyhow, receptors of any kind are just proteins which behave in specific ways when a ligand binds, be it changing conformation, on a more simple level, from an ion channel (composed of protein subunits) being closed in it's resting state, and when bound by an (agonist) ligand, changes it's 3D shape to allow passage of ion flux currents, to complex arrangements of interacting, but separate proteins, such as a receptor protein associating with a G-protein, which when the receptor is activated, binding and hydrolyzing guanosine triphosphate (when bound to GTP a G-protein is active, when bound to the diphosphate, they are in a quiescent state), and through the G-protein, multiple intracellular cascades of chemical messengers can be activated, which in turn, modulate gene transcription in the appropriate way.

oh that makes sense. So CRHR1 ligand is CRH and can only be activated via CRH? once crh is made in the pvn the CRH then goes on to activate CRHR1/CRHR2 etc receptors which are located all over the brain and body .
but
What do they mean by CRF/CRH mRNA expression in the amygdala etc? I thought CRH is first created in the PVN from the mRNA . does the CRH protein break up back to mRNA before it goes to different locations in the brain then go back into a CRH protein again?.. Or does mRNA just mean messanger to the xx area?

 

[trainman04]

so High CRH protein in the PVN hypothalamus is due to lacking enzyme regulating it and which overactives its receptors(Crhr1 in this case). You can have high surface expression but only so much can activate CRHR1 at once so that to CRH waiting in position or being used for something else? I was under the impression that the PVN was tightly protected or someth is that true?

If my ''rat'' has high CRH-CRHR1 signaling activation in the PVN of hypothalamus.
How would I fix this issue? Reduce the mRNA for CRH (clomipramine)? or with valproate or carbamazepine which inhibits CRH secretion in the hypothalamus?

all these terms: expression,secretion, activity, release,concentrations etc are they all the same meaning in the end? Inhibit, reduce, decrease ,lower??? alll same?


-Propylthiouracil (Propylthiouracil (PTU)-induced hypothyroidism caused a significant reduction in CRH gene transcripts in the paraventricular nucleus of male rats)

-Valproate (decreased CRH release in rats) + (Valproate treatment for one week led to decreased CRH concentrations in several brain regions, including the amygdala and he paraventricular nucleus of the hypothalamus)

-Carbamazepine (Although CBZ has been shown to inhibit hypothalamic CRH secretion in vitro) cant find a study where in the hypothalamus carbamazepine inhibits CRH.... it is important that is in the PVN right?

-Clomipramine (It was found that clomipramine lowers CRH mRNA expression in the PVN by 74%, regardless of stressor conditions)

-Tiagabine (blockade induced a setpoint-shift of the stress hormone system toward lower levels as indicated by decreased plasma corticosterone concentrations and attenuated gene expression levels of corticotropin-releasing factor in the paraventricular nucleus of the hypothalamus)

Which 5 of these would you suggest for my ''rat''? Is gene expression and gene transcripts same as CRH mRNA? or before that? DNA ? > mRNA > protein?

Does it matter where you reduce CRH for example median eminence or PVN? if you reduce in median eminence does that mean the CRH had the chance to go to other places becuase the median eminence is not where CRH is created first?


So decrease CRH in PVN = less CRHR1 activity right?
so Valproate = Key?

(half life 9-16 hours tho...)

 

[sekio]

I suggest you don't fuck with gene transcription at all, unless you want to mess around with e.g. antisense RNA/DNA in cell cultures, anything that effects protein synthesis will have a rather systematic toxic effect. Look up how ricin kills people.

all these terms: expression,secretion, activity, release,concentrations etc are they all the same meaning in the end?

Good lord, no. You really should be reading texts on cellular biology rather than faffing about in the darkness here. Humans are just too complex to reductionistically blame mental/social problems on the (mis)transcription of a single protien.

 

[trainman04]

I suggest you don't fuck with gene transcription at all, unless you want to mess around with e.g. antisense RNA/DNA in cell cultures, anything that effects protein synthesis will have a rather systematic toxic effect. Look up how ricin kills people.



Good lord, no. You really should be reading texts on cellular biology rather than faffing about in the darkness here. Humans are just too complex to reductionistically blame mental/social problems on the (mis)transcription of a single protien.

what about the other things I have said am I right in them? Less CRH equals less CRHR1 activity right. can CRHR1 be activated with urocortin or is that uncommon?

what I meant when I said they are all the same I mean in a way they all are in the process before the next step . If you reduce activity you reduce the other.

i didnt claim to be any expert on biology i will admit that, Im just intrested in this CRH-CRHR1 stuff ,besides that I have 0 experience in this field.

Reducing gene transcript/expression etc and mRNA is like the same just gene transcript is a few steps before so no point in trying gene transcript the mRNA will do with clomipramine and im sure clomipramine is way stronger (74%('). Maybe it would be beneficial in the case of gene duplication?

but Valproate or carbamazepine is what im looking for? I dont know were in the hypothalamus carbamazepine inhibits CRH but since it is closelly related structually to imipramine which inihibits CRH mRNA (up to 37% )I assume carbamazepine inhibits somewhere in the PVN. Becuase it is important that it effects the PVN right becuase thats where CRH is made first and spreads out.
im still confused about CRH mRNA in the amygdala .. Is CRH created in the amygdala also or is it sent from the PVN?

 

[sekio]

I think you need to treat your anxiety based upon first principles rather than placing all your hopes in one genetic marker out of possibly thousands.

CRFR₁ can indeed be activated by urocortin as well as CRF, and presumably other homologous protiens that are similar enough to interact at the active site of the receptor.

Becuase it is important that it effects the PVN right becuase thats where CRH is made first and spreads out.
im still confused about CRH mRNA in the amygdala .. Is CRH created in the amygdala also or is it sent from the PVN?

CRH is produced in all sorts of parts of the brain, look at the wiki RNA location map for CRH ignoring the fact the placenta is super-saturated with it, you can see the thalamus, hypothalamus, cingulate cortex, whole brain etc all produce mRNA for CRH and therefore also produce CRH. It isn't produced in a single location in the brain, rather there are specific cells that will produce it that are distributed throughout.

i didnt claim to be any expert on biology i will admit that, Im just intrested in this CRH-CRHR1 stuff ,besides that I have 0 experience in this field.

I'm not a master mechanic but I don't try to tell the guy at the VW service center my kooky theories about injector timings and turbo wastegate settings when it's not running right; I let the professionals make the diagnosis... see the analogy here?

There have been drugs developed that act as CRFR₁ antagonists, that is, they block the effects of CRF at the receptor. The two notable ones are antalarmin and pexacerfont, however trials have proved that neither is effective as an axiolytic despite their proven effect at blocking the activity of CRFR₁.

 

[trainman04]

I think you need to treat your anxiety based upon first principles rather than placing all your hopes in one genetic marker out of possibly thousands.

CRFR₁ can indeed be activated by urocortin as well as CRF, and presumably other homologous protiens that are similar enough to interact at the active site of the receptor.

CRH is produced in all sorts of parts of the brain, look at the wiki RNA location map for CRH ignoring the fact the placenta is super-saturated with it, you can see the thalamus, hypothalamus, cingulate cortex, whole brain etc all produce mRNA for CRH and therefore also produce CRH. It isn't produced in a single location in the brain, rather there are specific cells that will produce it that are distributed throughout.

From Wikipedia: ''CRH is produced by parvocellular neuroendocrine cells within the paraventricular nucleus of the hypothalamus and is released at the median eminence (the median eminence is the structure where secretions of the hypothalamus (releasing and inhibiting regulatory hormones, known as "hypophysiotropic hormones") collect before entering the portal system emptying into the general circulation) from neurosecretory terminals of these neurons into the primary capillary plexus of the hypothalamo-hypophyseal portal system. The portal system carries the CRH to the anterior lobe of the pituitary, where it stimulates corticotropes'' ''CRF₁ is activated through the binding of CRF or a CRF-agonist'' ''The corticotropin-releasing hormone receptor binds corticotropin-releasing hormone, a potent mediator of endocrine, autonomic, behavioral, and immune responses to stress''
''Corticotropin-releasing hormone receptor 1 has been shown to interact with Corticotropin-releasing hormone^[10][20] and Urocortin.^[21] ''

I assume CRH is made in the PVN trough DNA > mRNA > CRH but then the CRH is also distributed from the PVN in form of mRNA cells to other locations. Which then goes to the amygdala (or any other place) the CRH mRNA becomes CRH RNA (the m is just messanger) once it is arrived at desired location then the RNA becomes CRH protein which activates and binds to CRHR1 receptors. I assume CRHR1 is primarily activated by CRH and CRHR2 is more activated by urocortin etc But CRHR1 can be activated by urocortin but its rare or insignificant.


So if we take Carbamazepine for example or Valproate which say inhibit CRH release in the PVN. Now those two would inhibit CRH release just in the PVN but the CRH mRNA would continue on to other locations. What effect inibiting CRH in the PVN has I don't know (decrease CRHR1 activity in the hypothalamus?) but to reduce CRH and CRHR1 activation throughout the brain one would need to decrease the mRNA starting from the PVN becuase that is were it starts. Which Clomipramine reduces by up to 74% in the PVN. Which would decrease signaling to CRH and would decrease CRHR1 activity in all brain tissues etc.

specific cells that will produce it that are distributed throughout.

You are talking about the mRNA right which first starts in the PVN? which clomipramine reduces by up to 74% so these specific mRNA CRH cells will never have the chance to reach other locations or 74% less will have the chance to reach which leads to less CRHR1 activation.
Or do you mean there are specific cells (RNA) that are all over the brain which can produce CRH but the key messanger mRNA has to signal them for it to be made right? Becuase if you reduce CRH Messenger RNA from the PVN then it never has the chance to signal the CRH to be made in the amygdala etc and never binds to CRHR1.

PVN Makes CRH but it also signals CRH mRNA towards other brain tissues trough the hypothalamo-hypophyseal portal system to start create their own CRH and which then binds to its receptors. am I on the right track?

 

[trainman04]

Im just so confused. So CRH RNA is made in the amygdala, PFC etc.. So which one place would one need to target to decrease anxiety feelings? the amygdala? So a drug that inhibits CRH in the amygdala which decreases CRHR1 activity. Would the drug need to reduce CRH or reduce the CRH RNA?

check this study out : https://www.psypost.org/2017/02/res...rns-chronic-stress-pathological-anxiety-47544
''In the new study, published today in the journal Biological Psychiatry, the researchers investigated the interaction between the stress-promoting (CRF) and stress-constraining (eCBs) mechanisms in the central nucleus of the amygdala, a critical brain region involved in mediating emotional reactions. The findings suggest that overactive CRF signaling in this region produces a wide range of effects that override the stress-reducing capabilities of a major eCB called N-arachidonoylethanolamine (anandamide), turning chronic stress into unchecked, or pathological, anxiety.''..
''
The researchers studied rats that were genetically selected for higher alcohol drinking and also display an anxiety-like phenotype. These rats exhibit a mutation in a gene called Crhr1 that increases CRF (type 1) receptor signaling.
Using behavioral, neurochemical and electrophysiological approaches, the researchers found that increased CRF signaling led to elevated activity of the anandamide clearance enzyme fatty acid amide hydrolase (FAAH). Increased CRF was also associated with drops in anandamide levels in the central nucleus of the amygdala. Together, increased FAAH activity and decreased anandamide signaling reduce inhibitory control of excitatory neurotransmission in this critical region, and lower the brain’s ability to regulate stress and anxiety.
The researchers concluded that long-term dysregulation of CRF-FAAH mechanisms in the amygdala keeps anandamide from doing its job. Without anandamide to balance out the system, the brain is primed to react to stress.''


So it has to been in the central nucleus of the amygdala? valproate decreases CRH in the amygdala but doesen't say where (that I can find).
The rats has a mutation in CRHR1 which makes excess CRH bind to it which leads to low lvls of anandamide and low lwls of it in the central nucleus amygdala.

Do you know of any drugs that lower CRH / CRH RNA in the central nucleus of the amygdala? Or does my previous statement work with the clomipramine?

Where would one need to target to decrease CRH -CRHR1 activation all over the brain? surely decreasing the MRNA from the source first in the PVN does that? or lemme ask this what good does decrease CRH mRNA do in the PVN? would that decrease CRH all over the brain cause less CRH has the chance to reach the hypothalamo-hypophyseal portal system?

 

[sekio]

You might have missed, drugs that specifically block the action of CRHR1 in all brain tissues have been tried and don't work any better than placebo as anti-anxiety agents.... so treatment with carbamazepine or valproate won't be producing their effects via mediation of CRH at all but rather other mechanisms entirely.

 

[Coolwhip]

I think you are reading to much into the word "mutation", it doesn't necessarily mean something is wrong or broken, just different from the majority of the population, it's not necessarily indicative of a problem and with the plethora of checks and balances built into our neurological systems it doesn't mean it is affecting your psyche at all. Your brain is a complex system with all sorts of compensation mechanisms built in, rather than cause some snowballing effect which is ruining your life it is more likely your brain has already adapted to the change.

But, even IF said gene mutation is affecting the CRHR1 receptor in a significant way and is somehow contributing to your anxiety that doesn't mean fucking with CRH is the proper course of treatment.

 

[trainman04]

But, even IF said gene mutation is affecting the CRHR1 receptor in a significant way and is somehow contributing to your anxiety that doesn't mean fucking with CRH is the proper course of treatment.

of course it is, if it is ruining your day to day life and you cant function and in a constant anxiety state 24/7. I just dont understand why you guys cant tell me if i am right so I can go on my way.

AM I right in that reducing CRH mRNA in the PVN will lower CRH+CRHR1 all over the brain?

DNA > sends CRH RNA in form of mRNA (messenger) to PVN which is heavily protected by the BBB > Some of the CRH mRNA turns into RNA and becomes CRH protein in the PVN but also some mRNA continue on trough the hypothalamo-hypophyseal portal system to other locations (amygdala,hippocampus,PFC etc) and become CRH RNA which becomes CRH protein then binds to CRHR1 receptors?

 

[Coolwhip]

Of course it is? Are you kidding me? That is so reductive it is laughable, it is analogous to saying of course lobotomies are the proper course of treatment for schizophrenia because we have identified which brain regions are malfunctioning. No one here is going to help you hurt yourself no matter how much you demand it. Seek help from a professional, both psychiatrists and psychologists, if the first doc isn't able to help you find another.

But, just so you can go on your way, no, almost nothing you are posting is right, in fact it is all gibberish.

 

[trainman04]

''it is analogous to saying of course lobotomies are the proper course of treatment for schizophrenia because we have identified which brain regions are malfunctioning.''

what are you even saying?
People with low serotonin cant take an SSRI becuase?? they are doing it without a doctor ? where do you think am getting the medications from? I have no idea what you are arguing. Am I not allowed to treat excess CRH-CRHR1? WHY ARE YOU SO HOSTILE FOR NO REASON? Do you have schizoprehnia? Maybe you are the one that needs help. Not with lobotomies (stupid analogy stupid answer) but I suggest with antipsychotics and therapy.


You say everything ive said regarding CRH is gibberish but I dont think so. the door is that way --> close it after yourself. I dont want any help from you your delusional and overeact like a woman for no reason.(illogical)

 

[Neithman]

there are 1000s of proteins,receptors etc humans are too complex too say that a problem solely stems from there being a problems from too low levels of a certain protein,neurotransmitter.You convinced yourself that your anxiety problem is because you have some kind of mutation in your brain,that causes your problems.I suggest behaveorial therapy

 

[Neithman]

also sites like selfdecode just make people more anxious about their brain and that something isnt right with you,everyone has mutations in their genome

 

[trainman04]

there are 1000s of proteins,receptors etc humans are too complex too say that a problem solely stems from there being a problems from too low levels of a certain protein,neurotransmitter.You convinced yourself that your anxiety problem is because you have some kind of mutation in your brain,that causes your problems.I suggest behaveorial therapy

im not allowed to ask biology questions?

 

[trainman04]

yes there are many different proteins etc but if you think for one second CRH is the body stress signal step and which activates CRHR1 and you can go read a lof of studies proving these two are the most involved in feelings of anxiety.

''Lithium administration decreased CRF(1) mRNA expression in both the amygdala and frontal cortex, but CRF(1) receptor binding also remained unchanged.''

guess the receptors have to be made somehow