GIRK Channels

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

Unread post by Ghost »

I found something that could change the way that we think of desensitization of 5HT1A autoreceptors. The most exciting thing is that it gives some clarity to the problem other than "oh, yea, they desensitize". It's also very new because it would suggest that the problem occurs between the receptor and the ion channel. I'll paste in some things I posted about Metabotropic Receptors and GIRK potassium channels earlier today.

I highly recommend reading this study if you want to understand what I am talking about going forward. You can skip the methods, but the abstract, intro, results and discussion are really great.

"There are two types of Neurotransmitter receptors in the brain:

Metabotropic Receptor: Receptor that acts on ion channels through a secondary messenger. The ion channels that it controls are not directly attached to the protein that binds the neurotransmitter. These receptors do not have ion channels as part of their structure; instead, they affect channels by the activation of intermediate molecules called G-proteins.

Ionotropic Receptor: Receptors that are linked directly to ion channels. Thus ionotropic receptors combine transmitter-binding and channel functions into a single molecular entity.

A good way to visualize these two types of receptors:

http://www.ncbi.nlm.nih.gov/books/NBK10855/

G protein Coupled Receptors (GPCRs): Metabotropic Receptors that span the lipid bilayer of the cell with transmembrane helices. They hold three subunits of the G-protein. After activation, the subunits dissociate from the receptor as a result of a Conformational Change of the receptor. Now these loose subunit can find another target protein, and regulate its action. This could be Could be Enzymes, or ION CHANNELS.

In our case, the Neurotransmitter is 5HT, and the receptor is the 5HT1A receptor, which uses secondary messengers to the open ion channels that send messages in the cell. This means that the 5HT1A receptor is a METABOTROPIC receptor (and a GPCR). In the presynaptic cell, 5HT1A autoreceptors open K+ (Potassium) channels that Hyperpolarize (make more negative) the cell. Cells that are more negative are less likely to fire, so in this specific case hyperpolarizing a 5HT RN cell would inhibit release of 5HT to postsynaptic targets. This is how activation of the 5HT1A AR decreases the amount of 5HT released in its projections across the brain.

In 5TH1A neurons in the RN, this is done with GIRK (and maybe GIRK2) channels. Coupling to GIRK is reduced by chronic treatment with the SSRI fluoxetine (Prozac)."


http://jn.physiology.org/content/98/1/1 ... t.pdf+html

"Because GABA-B receptor-induced GIRK responses were also suppressed,fluoxetine does not appear to desensitize 5-HT1A receptors but rather one of the downstream components shared with GABAB receptors"

"This suggests that fluoxetine treatment affects 5-HT1A receptor functionality downstream of the 5-HT1A receptor and at a level of the signaling pathway that is shared with the GABAB receptor to the GIRK pathway."
- Medical Student & Friendly poltergeist - Lexapro Sept '14. [Hx] [PSSD Lab] [r/PSSD] [Treatment Plan] - Add "Ghost" in replies so I see it :)
fasttrack1982
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Re: GIRK Channels

Unread post by fasttrack1982 »

Ghost keep up the good work researching, and hypothesizing. The more you and other PSSD sufferers understand the brain, the better chance we will have at finding effective treatments.
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Ghost
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Re: GIRK Channels

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thanks! Yea I think that the solution to this problem may have to come from within the PSSD community. I've worked extremely hard this past week and am putting together another paper of my own.

I've worked out the outline of a theory that fits with all the evidence we already have, and gives an explanation of why the 5HT1A autoreceptor has stayed desensitized. It also explains why some people don't get PSSD until after they stop the drugs. I'm probably a few months away from finalizing the entire thesis, but it revolves around the G-Proteins that work between the activation of the receptor, and the opening of these K+ channels. It also takes into account the role of the postsynaptic receptors, which I think have been ignored a lot till this point. I really think I may have solved it. PSSD that is. But even if I have, there is still a lot of work to be done to figure out the details, and I don't want to get ahead of myself, because every time I've done that in the past I've been disappointed.

I'm now of the strong impression that the receptor itself hasn't been damaged, but it's the connection from the receptor to the channel that has been harmed. Sonny has long used a broken button on a TV remote to describe the Autoreceptor desensitization, and in this analogy, it would be the wires from the button to the circuit board that receives the signal. I think the next step for my research is taking a deeper look into what controls the expression of these g-protein subunits in the DRN, and what can keep those levels changed after the SSRI has been suspended.
- Medical Student & Friendly poltergeist - Lexapro Sept '14. [Hx] [PSSD Lab] [r/PSSD] [Treatment Plan] - Add "Ghost" in replies so I see it :)
escitalopramsucks
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Re: GIRK Channels

Unread post by escitalopramsucks »

Thank ou ghost!!!
For all te dedication and time...
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Sonny
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Re: GIRK Channels

Unread post by Sonny »

This is brilliant stuff! I'm loving this and the posts in your locked topic. This is amazing research and exactly what we need.
iull1k
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Re: GIRK Channels

Unread post by iull1k »

A thought came to me these days about ion channels, C-fibers and peripheral neuropathies.

http://www.psas.nl/artikelen/mannen.pdf

http://www.psas.nl/artikelen/TENS.pdf
" Selective serotonin reuptake inhibitor (SSRI)–induced genital anesthesia may be a result of the increased activation of spinal 5-HT receptors, which in turn increase inhibition on pudendal C fibers [32].9. SSRI-withdrawal-induced ReGS or spontaneous orgasm [33,34] may be a result of reduced activation of spinal 5-HT receptors, which in turn disinhibit pudendal C fibers."

https://en.wikipedia.org/wiki/Peripheral_neuropathy
https://en.wikipedia.org/wiki/Dysautonomia
https://en.wikipedia.org/wiki/Group_C_nerve_fiber
"[5] The abnormal activity of the damaged nerves is associated with the increased presence of mRNA for voltage-gated sodium channels.[12] Irregular grouping of these channels in sites of the abnormal activity may be responsible for lowering the activation threshold, thus leading to hyperactivity.[12]"
"Capsaicin activates C fibers by opening a ligand-gated ion channel and causing an action potential to occur."

"http://rxisk.org/complex-withdrawal-model/
Peripheral neuropathies & C-fibers"

There can be some true in this article. http://www.pssdforum.com/viewtopic.php?f=6&t=578

What if our problems are related not to amount of serotonin but to chaotic 5HT UP/Down regulation of receptors which lead to dysautonomia? Just look at dysautonomia or C-fibers symptoms and you will see each withdrawall symptom. I talk about this because it's me who have PSSD and PGAD in the same time, and i'm not alone. If PGAD diminished under TENS and PSSD under FSM then there can be a part of true. We are not broken , our C-fibers may not be damaged but just inhibited/disinhibited by a serotonergic process. Maybe Healy's thoughts are not only bullshit.
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Ghost
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Re: GIRK Channels

Unread post by Ghost »

iull1k wrote:A thought came to me these days about ion channels, C-fibers and peripheral neuropathies.

http://www.psas.nl/artikelen/mannen.pdf

http://www.psas.nl/artikelen/TENS.pdf
" Selective serotonin reuptake inhibitor (SSRI)–induced genital anesthesia may be a result of the increased activation of spinal 5-HT receptors, which in turn increase inhibition on pudendal C fibers [32].9. SSRI-withdrawal-induced ReGS or spontaneous orgasm [33,34] may be a result of reduced activation of spinal 5-HT receptors, which in turn disinhibit pudendal C fibers."

https://en.wikipedia.org/wiki/Peripheral_neuropathy
https://en.wikipedia.org/wiki/Dysautonomia
https://en.wikipedia.org/wiki/Group_C_nerve_fiber
"[5] The abnormal activity of the damaged nerves is associated with the increased presence of mRNA for voltage-gated sodium channels.[12] Irregular grouping of these channels in sites of the abnormal activity may be responsible for lowering the activation threshold, thus leading to hyperactivity.[12]"
"Capsaicin activates C fibers by opening a ligand-gated ion channel and causing an action potential to occur."

"http://rxisk.org/complex-withdrawal-model/
Peripheral neuropathies & C-fibers"

There can be some true in this article. http://www.pssdforum.com/viewtopic.php?f=6&t=578

What if our problems are related not to amount of serotonin but to chaotic 5HT UP/Down regulation of receptors which lead to dysautonomia? Just look at dysautonomia or C-fibers symptoms and you will see each withdrawall symptom. I talk about this because it's me who have PSSD and PGAD in the same time, and i'm not alone. If PGAD diminished under TENS and PSSD under FSM then there can be a part of true. We are not broken , our C-fibers may not be damaged but just inhibited/disinhibited by a serotonergic process. Maybe Healy's thoughts are not only bullshit.
I mean, I will always remain open to other possibilities, it just seems a bit off for what I'd expect, and for what we've seen in treatments. I fail to see how these fibers could lead to loss of libido, or apathy, and how they explain the changes in hormone levels that many people with PSSD see.

C-fibers are a "sexy"/ "hip" topic in neuroscience at the moment. There is money going to fund research on it. When you talk about them at a conference, people will get excited.

You raise good points, and I'm glad you posted this, but I'm far from believing that these fibers are the main cause of our problem. This is because everything I've read on the AR theory fits with what we'd expect.

What would change my opinion?

For a start, if a lot of people with PSSD did FSM or whatever and felt immensely better. Then I'd have the confidence to start drawing connections, and try to piece it back to the SSRI.
- Medical Student & Friendly poltergeist - Lexapro Sept '14. [Hx] [PSSD Lab] [r/PSSD] [Treatment Plan] - Add "Ghost" in replies so I see it :)
iull1k
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Re: GIRK Channels

Unread post by iull1k »

I think we misunderstood. I mean i don't doubt AR desensitization. But this is about brain activity. I said about PGAD and other skin sensations like numbness, tickling and so on. I don't know how about other but i have reduced pain sensations, reduced temperature sensations, tickling and last months i noticed that i have strange genital sensations that this weeks i found that it's called PGAD! http://www.psas.nl/en/doktoren.asp When i tried to search i saw that i'm not alone. Other have the same from SSRI, ondasteron (5HT3 antagonist) , Zolpidem (Gaba antagonist) , hysterectomy, prostatectomy, menopause (I think hormonal changes). When i searched about PGAD i found some Waldinger researches where he said about Spinal 5HT and PGAD. Just look how topical lidocaine works http://emedicine.medscape.com/article/1831870-overview , the same mechanism can hide SSRI. The point is not only brain 5HT is involved, there is peripherial action too. If you will study how sensory , auditive, visual and others stimulants are mediated to brain you will find about C, A- fibers, general visceral afferent fibers (GVA),Preganglionic nerve fibers and so on. They all can be mediated trough spinal 5HT, NE, DA modulation like Tramadol numb pain trough spinal 5HT
(http://journals.lww.com/anesthesia-anal ... of.33.aspx)

I had windows when all was different, touch, pain, temperature sensations, hearing, visual perception even smell and cognitive abilities. I even had one week back a surge of libido. This was amazing guys. I don't want to say that this nerve fibers are damaged, NO!!, i want to say that they are inhibited through unknown mechanism. I really think about spinal 5HT in this case. Yes there is a lot of work and and nearly no scientic evidence but this is the most real cause of this peripherial sensations.
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Ghost
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Re: GIRK Channels

Unread post by Ghost »

Knockout of GIRK1 channels reduces anxiety behavior. Very interesting.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3052907/
- 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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Ghost
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Re: GIRK Channels

Unread post by Ghost »

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4212061/ This is next on my list to read. I really wish that I had some other people to bounce ideas off of. I think I'm continuing to close in on the causes of PSSD.

PIP2: It would explain some things: First off, It is a derivative of inositol.
https://en.wikipedia.org/wiki/Phosphati ... AG_pathway

It’s an inositol strain of phospholipid, and can regulate GIRK channels. Gq G GPCR couplers stimulate Phospholipase C (PLC), and deplete Plasma Membrane levels of PIP2. Desensitizing the channels. It may/is likely not (knowing the extreme complexity of biological systems. Also, even if it was the cause, finding ways to artificially regulate it or test it would be very, very, hard and expensive) be a huge lead in the cause of PSSD, but it possibly could be all the marbles. Think, and just let me fly a theory out here quick, with no backing of it being right... 5HT2 receptors are Gq G coupled. Wikipedia even says: "The 5-HT2A receptor is known primarily to couple to the Gαq signal transduction pathway. Upon receptor stimulation with agonist, Gαq and β-γ subunits dissociate to initiate downstream effector pathways. Gαq stimulates phospholipase C (PLC) activity" - https://en.wikipedia.org/wiki/5-HT2A_receptor

Ok so at that point you have a stimulus from SSRI increasing 5-HT through inhibiting SERT. You get a raise in 5HT2 accepting 5-HT, and subsequent activation of PLC. This depletes PIP2, which desensitizes the GIRK pathway. The pathway can't recover because "Activation of PLC also leads to stimulation of PKC". and PKC decreases the activity of GIRK. Anyways, if this by some small chance happened to be the case, it would serve as the desensitization of the GIRK channel. Then it wouldn't matter how many times the 5-HTA autoreceptor was bound, because the GIRK channel wouldn't be able to hyperpolarize the Presynaptic cell. The entire system would be stuck, and absolutely fucked. Functional desensitization of the 5HT1A AR. Everything downstream would make sense if you disinhibited the DRN. PSSD would be solved in theory.

I hope that it would be that easy. Finding the cause of desensitization of Antidepressants could change the world, and could possibly win you a nobel prize.... I shouldn't get ahead of myself.... :) ;). Anyways, you guys get the idea. A lot of this shit is me spewing ideas that I'm not sure of, but hopefully someone on here reads what I wrote, understands why it is wrong, and chews me out in a comment. Then we could go back to the drawing board and keep pounding this thing out. There is a lifetime of work in this field...

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3052907/
"In addition to these modulators, changes in the levels of the membrane phospholipid phosphatidylinositol 4,5 bisphosphate (PIP2), can regulate the activity of GIRK channels58-60. Stimulation of GPCRs that couple to Gq G proteins stimulate phospholipase C (PLC) and deplete plasma membrane levels of PIP2, leading to desensitizing GIRK currents 55,61,62 (but see ref63). Activation of PLC also leads to stimulation of PKC, enabling cross-talk of these two pathways (PIP2 depletion and PKC phosphorylation) in the regulation of GIRK channels55,56."
- 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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