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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Re: GIRK Channels

Unread post by Ghost »

In response the the first article that you posted (MUMA and VAN DE KAR, 1996). It concludes the Go and Gi2 alpha subunits are probably what is being used by 5HT1A autoreceptors. These decrease within 3 days in the midbrain (that has the DRN). Then in 7-14 days they saw the Gi3 and Gi2 decrease in the Hypothalamus (Which is a 5-HT projection site from the DRN). This is very interesting, and further narrows the search to Go and Gi2 alpha subunits binding to the 5HT1A AR in the DRN. wow...we've gotten a lot closer to the cause I think...

Regardless, there is still something bothering me. It's the Gby dimer that directly activates GIRK channels to inhibit neurons...so why would decreases in the alpha subunit matter for the autoreceptor? You would think that it wouldn't...Or that the entire story still isn't being told.

Back to the books, I suppose :)
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Ghost
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Re: GIRK Channels

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Check this out.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2890727/

"Here, we define a mechanism downstream of 5-HT1A receptors that mediates antidepressant-like behavior and is profoundly and selectively enhanced by genetic disruption of regulators of G protein signaling (RGS) activity at Gαi2. Animals rendered insensitive to RGS protein regulation "

"RGS-insensitive mice were also 5–10 times more responsive to the antidepressant-like effects of the SSRI fluvoxamine"

"In contrast, the antidepressant potency of agents acting through nonserotonergic mechanisms was unchanged"

My conclusion: We may have found the little bastard. He's been hiding from us for years.

I now move my research focus to understanding the expression of these subunits, and how this could be reversed. Some of my writing will be put on hold as a result. I'll return to it once I better understand what we've discovered.
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electric16
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Re: GIRK Channels

Unread post by electric16 »

Go Ghost Go!

(Not being sarcastic, genuinely impressed and excited by your enthusiasm and commitment)
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Sonny
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Re: GIRK Channels

Unread post by Sonny »

This is awesome. You're making a lot of progress. This is some complicated stuff too. A couple these things I'm having trouble following. I get the main idea though.
ssinus
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Re: GIRK Channels

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In agreement, the antibody capture method revealed that a subset of mACh receptor agonists could stimulate robust [35S]-GTPγS binding to both Gαq/11 and Gi1-3 proteins.
http://www.pa2online.org/Vol2Issue4abst028P.pdf
http://jpet.aspetjournals.org/content/3 ... 5.full.pdf

I have found couple of studies claiming that the Muscarinic acetylcholine receptor agonists may have positive effects on activation/binding of G proteins.
What do you think, worth a try ? I havent studied it in that details as Ghost but probably it might be some connection ?
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Ghost
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Re: GIRK Channels

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ssinus wrote:
In agreement, the antibody capture method revealed that a subset of mACh receptor agonists could stimulate robust [35S]-GTPγS binding to both Gαq/11 and Gi1-3 proteins.
http://www.pa2online.org/Vol2Issue4abst028P.pdf
http://jpet.aspetjournals.org/content/3 ... 5.full.pdf

I have found couple of studies claiming that the Muscarinic acetylcholine receptor agonists may have positive effects on activation/binding of G proteins.
What do you think, worth a try ? I havent studied it in that details as Ghost but probably it might be some connection ?
I think that M1 and M3 receptors use the Gi/o pathway as well, so there are definitely correlations between the 2. I think the important differences are where the receptors are and what RGS proteins are regulating the G-proteins in a particular cell.


RGS proteins reconstitute the rapid gating kinetics of
Gbg-activated inwardly rectifying K1 channels

CRAIG A. DOUPNIK*, NORMAN DAVIDSON†, HENRY A. LESTER‡, AND PAULO KOFUJI

Contributed by Norman Davidson, July 17, 1997

G protein-gated inward rectifier K1 (GIRK)
channels mediate hyperpolarizing postsynaptic potentials in
the nervous system and in the heart during activation of
Ga(iyo)-coupled receptors. In neurons and cardiac atrial cells
the time course for receptor-mediated GIRK current deactivation
is 20–40 times faster than that observed in heterologous
systems expressing cloned receptors and GIRK channels,
suggesting that an additional component(s) is required to
confer the rapid kinetic properties of the native transduction
pathway. We report here that heterologous expression of
‘‘regulators of G protein signaling’’ (RGS proteins), along
with cloned G protein-coupled receptors and GIRK channels,
reconstitutes the temporal properties of the native receptor3
GIRK signal transduction pathway. GIRK current waveforms
evoked by agonist activation of muscarinic m2 receptors or
serotonin 1A receptors were dramatically accelerated by coexpression
of either RGS1, RGS3, or RGS4, but not RGS2. For
the brain-expressed RGS4 isoform, neither the current amplitude
nor the steady-state agonist dose-response relationship
was significantly affected by RGS expression, although
the agonist-independent ‘‘basal’’ GIRK current was suppressed
by '40%. Because GIRK activation and deactivation
kinetics are the limiting rates for the onset and termination of
‘‘slow’’ postsynaptic inhibitory currents in neurons and atrial
cells, RGS proteins may play crucial roles in the timing of
information transfer within the brain and to peripheral
tissues.
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Ghost
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Re: GIRK Channels

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But that leads me to what I've been reading the past few days actually...

I don't think that the DOUPNIK et al. study from 1997 is accessible for free other than the abstract, which is a shame because it has some good stuff in there. Here is a quote from it though:

RGS Specificity and GIRK Channel Kinetics. The results of
this study demonstrate that coexpression of certain RGS
proteins (i.e., RGS1, RGS3, or RGS4) with GIRK channels
and Gaiyo-coupled receptors reconstitutes the rapid gating
characteristics of native atrial and neuronal GIRK currents.
Northern blot analysis indicates that RGS3 and RGS4 are
highly expressed in the heart and brain, respectively (2, 3), and
therefore are candidates for conferring the rapid kinetics of
atrial and neuronal GIRK channels. RGS1 on the other hand,
which was as effective as RGS3 and RGS4 in accelerating
GIRK currents in Xenopus oocytes, is a mitogen-activated
immediate–early gene expressed in B lymphocytes and not
detected in the heart or brain (26). RGS2, also an immediate–
early gene expressed in malignant hematopoietic and nonhematopoietic
cells (27), had no significant effect on GIRK
current waveforms. Recent experiments show that RGS2 does
not interact with Gai2, Gai3, or Gao subunits in vitro under
conditions (i.e., GDP-AlF4) that favor binding by RGS1,
RGS3, and RGS4 (28). Therefore, the lack of RGS2 effects on
GIRK kinetics may be explained by an inability to interact
effectively with Gaiyo subunits. The effect of RGS1 on GIRK
gating suggests that other RGS isoforms expressed in the heart
and brain (i.e., GAIP, RGS5, RGS7, RGS10), which interact
effectively with Gaiyo proteins, might also be expected to
accelerate GIRK channel gating.

This made me curious about RGS4, and its potential role in stopping DRN GIRK channels from hyper-polarizing the presynaptic cell.

Again, this narrows the search from RGS proteins in general, to RGS4.

Another literature search led me here:

http://www.fasebj.org/content/29/1_Supplement/618.11

"Specifically, we have shown that upregulation of cortical RGS4 (mRNA and protein) occurs in response to genetic disruption of RGS protein activity at the GTP-binding protein Gαi2 and following chronic administration of serotonin-selective reuptake inhibitors (SSRIs)."

This should make you lead forward in your chair. Admittedly, I'm not an expert on RGS4 yet, but up regulation of RGS4 COULD force shorter g-protein activation of GIRK channels in the DRN. How do we know that? Remember that Gαi2 plays a large role in 5-HT1A receptors (and in the antidepressant response - read above posts by me), which would desensitize the GIRK currents. This would lead to 5-HT1A Autoreceptors not responding to elevated 5-HT levels. The entire system would disinhibit, and you'd have all the downstream problems associated with PSSD.

This is currently my best guess on what I think has happened to us. Up-regulated RGS4 would explain it quite well.

I'll keep posting updates, and continue to encourage your thoughts.

:geek: :geek: :geek:
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Animus
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Re: GIRK Channels

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Full Doupnik study.
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Ghost
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Re: GIRK Channels

Unread post by Ghost »

^ Thanks!

Another line of evidence for this theory (and one that involves humans):

"Regulator of G protein signaling 4 is a crucial modulator of antidepressant drug action in depression and neuropathic pain models"

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3657820/

"RGS4 is regulated by chronic antidepressant treatment. (A) Antidepressant treatment promotes the expression of RGS4 in human NAc. qPCR analysis of postmortem NAc tissue from control, depressed-nonmedicated (subjects who were not on antidepressant medication at time of death), and depressed-medicated subjects [subjects treated with antidepressants (Table S1) at time of death] reveals that although RGS4 expression is not affected by depression per se, there is a nearly fourfold increase in RGS4 mRNA levels in subjects treated with antidepressants. The average postmortem interval was 16 h. The different groups were matched as closely as possible for race, sex, age, pH, postmortem interval, and RNA integrity number (n = 8 per group; see Table S1 for further information). (B) Similarly, DMI treatment (10 mg/kg i.p. twice a day for 2 wk) significantly increased Rgs4 protein levels in NAc of C57BL/6 mice. Mice were analyzed 24 h after the last drug injection (n = 3 per group; *P < 0.01, t test). DMI, desipramine; OD, optical density; SAL, saline."
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DoIt
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Re: GIRK Channels

Unread post by DoIt »

I'm only affraid that you find the cause but we don't have any necessary medicines to affect it...
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