GIRK Channels

This is a place to post research you have done on the topic along with your conclusions.
pete
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Re: GIRK Channels

Unread post by pete »

Depletion of PIP2 is also desensitizing TRPV1 channels.

https://en.wikipedia.org/wiki/TRPV1

This explains some more things.
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Ghost
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Re: GIRK Channels

Unread post by Ghost »

Thanks both Jaiho and pete for your thoughts. I am looking into those options as well as I continue my research. I think that 5HT2C is tied in for sure.

If anyone wants to stay up to date with what I'm writing, this may seem pretty random, but it's tied directly to PIP2. I know that 5HT2 receptors activate Gq alpha subunits, but I'm not sure about 5HT1A yet. I think so, but haven't looked into that enough.

So here's my thinking:

If I figure out the entire pathway that could desensitize GIRK channels, then I basically have a lot of possible candidates for fuck-ups due to SSRIs. I'll screen all of these downstream messangers to see if studies in the DRN have been studied on them and SSRIs. IF NOT, then I finally have a reason for new research that I feel is warranted: PSSD research if you will.

http://courses.washington.edu/conj/gprotein/ip3.htm
- Medical Student & Friendly poltergeist - Lexapro Sept '14. [Hx] [PSSD Lab] [r/PSSD] [Treatment Plan] - Add "Ghost" in replies so I see it :)
jaiho
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Re: GIRK Channels

Unread post by jaiho »

Another thing, way100635, a 5ht1a antagonist, actually does target the RN.
Subjects who took way100635 experienced self-transcendence and spiritual acceptance personality traits. Perhaps 5HT1A is our most important sexual & presence receptor and by blocking it in the raphe may help with PSSD.

http://www.ncbi.nlm.nih.gov/pubmed/14594742
http://www.ncbi.nlm.nih.gov/pubmed/19435548
http://www.ncbi.nlm.nih.gov/pubmed/19435548

Image

I think from above, that SSRIs would be quite nice if the appropriate receptors are antagonised. 5HT1A & 5HT2C.
So do this selectively, you'd take something like Lexapro (SSRI), Way100635 (5HT1A Antagonist), and Agomelatine/Nortriptyline (5HT2C / NRI)

way100635 can be purchased from tht but it's quite expensive.
pete
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Re: GIRK Channels

Unread post by pete »

trpv1 channels definetely have to be involved somehow.
Since i have done this low dose paxil experiment. I get lot of great waves.
Often before i get hit by such a wave. I get tingling on the body.
You know this tingling after eating spicy food? It's exactly the same.

And thank you a lot Ghost for your work. It gives me some hope on dark days.
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Ghost
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Re: GIRK Channels

Unread post by Ghost »

This is important.

Different 5-HT receptors use different cascades. It's the 5-HT1A that is using Gi/o alpha subunits to do things (Adenyl Cyclase in this example), and then the beta/gamma dimer is activating the GIRK channels to hyperpolarize (In the case of the 5HT1A AR).

My guess is that somewhere in this shit-show is where desensitization truly occurs.
- Medical Student & Friendly poltergeist - Lexapro Sept '14. [Hx] [PSSD Lab] [r/PSSD] [Treatment Plan] - Add "Ghost" in replies so I see it :)
GIXXER
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Re: GIRK Channels

Unread post by GIXXER »

How expensive is way100635, what dosage would be recommended, and what about trying it on its own?
jaiho
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Re: GIRK Channels

Unread post by jaiho »

It's $450 a gram at tht.co
Bloody expensive, but might be ok if small doses work. But i dont know dosing or bioavailability.
The study above shows that it increases sexual desire with an SSRI but not necessarily by itself. Confusing.
maybe this applies to normal rats with a healthy 5ht1a system. a 5ht1a antagonist may reverse PSSD, but theres not enough info out there.
GIXXER
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Re: GIRK Channels

Unread post by GIXXER »

At this point in my life it would be pennies on the dollar to try. Its does sound promising but the thought of going back on a SSRI sends shivers up my spine.
forexworld12
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Re: GIRK Channels

Unread post by forexworld12 »

Ghost wrote:Thanks both Jaiho and pete for your thoughts. I am looking into those options as well as I continue my research. I think that 5HT2C is tied in for sure.

If anyone wants to stay up to date with what I'm writing, this may seem pretty random, but it's tied directly to PIP2. I know that 5HT2 receptors activate Gq alpha subunits, but I'm not sure about 5HT1A yet. I think so, but haven't looked into that enough.

So here's my thinking:

If I figure out the entire pathway that could desensitize GIRK channels, then I basically have a lot of possible candidates for fuck-ups due to SSRIs. I'll screen all of these downstream messangers to see if studies in the DRN have been studied on them and SSRIs. IF NOT, then I finally have a reason for new research that I feel is warranted: PSSD research if you will.

http://courses.washington.edu/conj/gprotein/ip3.htm
To begin to examine the mechanism of 5-hydroxytryptamine1A receptor desensitization, we determined levels of Gi and G(o) proteins in the hypothalamus, midbrain and frontal cortex by using immunoblots. The hypothalamic levels of Gi1 and Gi3 proteins were significantly reduced after 7 and 14 days of fluoxetine injections. The levels of G(o) and Gi2 proteins in the midbrain were significantly decreased after 3 days and remained reduced for the duration of fluoxetine injections. . The similarity in time course between fluoxetine-induced reductions in hormone responses to 8-OH-DPAT and the reduction in hypothalamic levels of Gi1 and Gi3 proteins suggests that a reduction in hypothalamic levels of Gi3 and/or Gi1 proteins plays a role in the gradual desensitization of 5-hydroxytryptamine1A receptors induced by fluoxetine.

http://jpet.aspetjournals.org/content/279/2/1035.short

A single day of paroxetine treatment did not alter the hormone responses to 8-hydroxy-2-(dipropylamino)tetralin. Repeated injections of paroxetine did not reduce the density of 5-HT1Areceptors in any brain region but did produce a gradual reduction in the levels of Gi and Go proteins in a region-specific manner. The time course of the paroxetine-induced reduction in the level of Gi1 and Gi3 proteins in the hypothalamus was similar to the effect previously observed with fluoxetine and was also similar to the time course of paroxetine-induced reductions in oxytocin and adrenal corticotropic hormone responses to 8-hydroxy-2-(dipropylamino)tetralin. In conclusion, these results suggest that blockade of 5-HT uptake sites produces a delayed and gradual desensitization of 5-HT1Areceptors in the hypothalamus. This desensitization is not due to changes in the density of hypothalamic 5-HT1A receptors. Reduction in the hypothalamic level of Gi3 proteins may play a role in the desensitization of 5-HT1A receptor systems. However, reductions in Gi1 or Goproteins cannot be excluded as potential mediators of the desensitization of 5-HT1A receptor systems.

http://www.sciencedirect.com/science/ar ... 9397006938

Abstract
Chronic treatment with the antidepressant fluoxetine may lead to changes in the properties of pre- and postsynaptic 5-HT1A receptors due to modifications in the receptor-G protein coupling process. We have evaluated, in rats, the effect of chronic fluoxetine (10 mg/kg/day) at brain 5-HT1A receptors using different techniques. The density of 5-HT1A receptors was unchanged in fluoxetine-treated rats vs. vehicle group. Stimulation of [35S]GTPγS binding induced by (±)8-OH-DPAT was significantly attenuated in dorsal raphe nucleus after fluoxetine (+3.7 vs. +31.2% in vehicle). The inhibition of dorsal raphe firing by (±)8-OH-DPAT (ED50 in vehicle = 2.1 μg/kg, i.v.) was also attenuated in rats treated with fluoxetine (ED50=4.7 μg/kg). In contrast, a significant increase on (±)8-OH-DPAT-induced stimulation of [35S]GTPγS binding was observed in CA1 (+53.4 vs.+20.2% in vehicle) and dentate gyrus (+105.7 vs. +52.6% in vehicle) but not in entorhinal cortex. Our data demonstrate that fluoxetine-induced desensitization of 5-HT1A autoreceptors occurs at G protein level.

http://www.sciencedirect.com/science/ar ... 0802003404

I don't know anything about these GPCR but The question is if these GPCR specifically Gi1 and Gi3 are down-regulated significantly by SSRI and desensitizes the 5-HT1A auto-receptors , HOW THE HELL DO WE INCREASE IT OR ACTIVATE IT ? . I mean if SSRI's are able to significantly decrease it there should be something that is able to increase it ,Ghost?
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Ghost
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Re: GIRK Channels

Unread post by Ghost »

Yea that is spot on and my next step was actually looking at studies like those. Thanks for finding them!

It's easy to get bogged down with so any studies that I have been reading. But I've decided to focus back on the 5HT1A receptor, and therefore, the Gi/o G-protein subunit and pathway, for now.

The 5-HT GPCRs can be divided into three major subgroups depending on which G protein signaling pathway they activate. 5-HT1 receptors couple mainly to
the Gi/o pathway; 5-HT4, 5-HT5, 5-HT6, and 5-HT7 receptors couple to the Gs pathway; and 5-HT2 receptors activate the Gq/11 pathway. The 5-HT3 receptors are ligand-gated ion channels.

http://www.ncbi.nlm.nih.gov/pmc/article ... -00040.pdf

I think that the best way to test these things going forward would be to run the experiments. First, it would need to be proven that the literature results could be repeated. I think a small number of mice or rats would be enough to show that SSRIs decrease Gi/o subunits. Additionally, It would be nice to repeat some of the studies that show mating behavior decreasing in mice/rats after being treated with SSRIs. Once both of these things were shown, you'd run a fuck-ton of drugs at varying doses to see if mating behavior would be restored from long-term treatment from these drugs. Obvious first candidates would be PSSD treatments that we've seen work before.

When a group of animals showed reversal of SSRI-induced changes in mating behavior, they would be sacrificed and their brains would be analyzed for changes in Gi/o subunit levels. Each group would also need at least 3 control groups to compare to. One wouldn't be given an SSRI at all. At the end of the study, they would be sacrificed, and Gi/o levels would be measured. This would show baseline w/o SSRI. The second control group would be sacrificed after being treated with SSRI to show that Gi/o levels decreased after treatment in that group. A third control group would be removed from the SSRI, but not given the treatment, to show that Gi/o levels could stay low after SSRI treatment.

If you had 10 animals in each group, you'd need 40 per drug, per dose.

As you can see, that gets tricky fast.

10 drugs = 400 animals
100 drugs = 4,000 animals

that's not taking into account the costs of buying the animals, housing them, paying people to care for them, buying the drugs, sacrificing the animals, equipment needed for Gi/o analysis...

It would cost a few million dollars. easily.

Obviously there are ways to cut that down a ton, but you'd lose the trust of the scientific community at large doing that.

If I won the lottery today, I would build my lab tomorrow. I finally know what I think we could research, but we are limited by options at the moment.

A great option is scouring the literature for people who have done things that are similar, and trying to find drugs that may reverse things.
- Medical Student & Friendly poltergeist - Lexapro Sept '14. [Hx] [PSSD Lab] [r/PSSD] [Treatment Plan] - Add "Ghost" in replies so I see it :)
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