Talk:Tropomyosin receptor kinase B

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Molecular Biology: MCB

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A summary of this article appears in Trk receptor.

Untitled

is this the memory molecule in this weeks New Scientist?

Pronunciation

Standard pronunciation is "track bee".

I love this sort of detail, and I wish more Wikipedia articles include things like this. Pronunciations, usage, and common parlance are sorely lacking in Wikipedia in general. That said, is there a reference for this "track bee" statement? Seems like the sort of claim that ought to be backed up. ThreeRocks (talk) 16:30, 14 December 2022 (UTC)[reply]

Potential antidepressant activity

Shouldn't we mention that studies have shown that Tropomyosin receptor kinase B seems to show significant antidepressant activity? Why do two of the links mention antidepressant activity, yet the terms "antidepressant" or "depression" are mentioned nowhere in the current version of this article? 173.88.246.138 (talk) 05:15, 6 June 2023 (UTC)[reply]

Antidepressants and psychedelics as TrkB modulators

It's recently been claimed by certain research groups that antidepressants and psychedelics act as TrkB positive modulators of variable potency and that this action mediates their antidepressant effects. While the papers are interesting, I've been very skeptical of these claims since they were published. They are simply very difficult to reconcile with a lot of other things we already know. The claim that the delayed onset of benefit of antidepressants is due to them slowly accumulating in the brain to a level that can adequately potentiate the TrkB particularly seems questionable to me.

Despite my skepticism, and I'm sure the skepticism of many researchers, I've never seen these claims challenged in the scientific literature before. However, I recently came across some very interesting comments on social media by psychedelic researcher Matthew Baggott about psychedelics and other drugs like 7,8-dihydroxyflavone (7,8-DHF) as TrkB positive modulators in which he casts major doubt on the findings.^[1]^[2] I thought that I'd share his comments here as they may have implications for the relevant Wikipedia content. We'll have to wait for more publications and see if anyone tries to replicate the findings and succeeds or fails of course. But if/when that happens, the relevant Wikipedia content may be in need of some refactoring. – AlyInWikiWonderland (talk, contribs) 02:01, 5 February 2025 (UTC)[reply]

References

^ u/MBaggott (7 January 2024). "[Comment(s)]". Reddit. Retrieved 5 February 2025. I think their first finding, that psychedelics are high affinity TrkB ligands, is simply wrong. They are assuming that HEK293T cells don't naturally express any 5-HT1 receptors, which would be a more plausible explanation for their results. Then their later LSD results use implausibly high concentrations that are unlikely to occur in vivo. I screened some tryptamines with TrkB PAM and agonist assays and did not see anything. [...] I can't explain all their findings. I imagine a lot of things can go wrong when you're measuring something as promiscuous as [3H]LSD. One that I screened was 5-MeO-MiPT, which anecdotally has antidepressant-like effects. It's also worth noting that Bonaventura et al failed to see any interaction of R,R-HNK, the paper's other putative ligand, with TrkB. The literature on TrkB agonists has been confusing since Boltaev et al 2017. Overall, I find a later downstream role for TrkB to be plausible but I've been waiting for someone else to replicate this alleged direct interaction. It should be easy to replicate and extend, yet no one has. [...] N-acetyl-serotonin is also in the category of alleged TrkB ligands people can't replicate. Although there is evidence that some small molecules have BDNF-independent TrkB-mediated effects, I'm not sure there's good evidence that any small molecule really is a TrkB ligand. If we could really repurpose the tryptamine scaffold and screen it against TrkB to get fast acting novel antidepressants, dozens of labs would be doing it and I think we'd already be seeing preprints. So we do need to wait, but the silence is becoming interpretable.
^ u/MBaggott (18 August 2023). "[Comment(s)]". Reddit. Retrieved 5 February 2025. I'm not really a 5-HT2A specialist, but several I know have expressed deep skepticism. Based on this paper, I went ahead and screened 5-MeO-MiPT at TrkB and found it is neither a PAM nor an agonist. So if the theory is correct, it's not true of all psychedelics. If you want a theory for why microdosing might work, the simplest answer may be that both antidepressant and psychedelic effects are mediated by 5-HT2A but that the EC50 for neuroplasticity/antidepressant effects is lower than the EC50 for frank psychedelic effects. I have a commentary piece under review that argues this. This idea is also consistent with Jason Wallach's excellent new preprint. [...] It's not surprising that many therapeutic agents act, at least in part, via TrkB/BDNF pathways. The surprising thing would be if they directly bind to TrkB. Boltaev et al 2017 suggest a lot of findings about direct TrkB stimulation may be wrong. They failed to find agonist or positive allosteric effects for a large number of molecules. [...] For me, direct TrkB interactions are a side quest since they are not relevant to entactogens. However, if you want to set that up, I'd gladly help defray costs and send you some compounds to screen! Yeah, the Boltaev paper is annoying in its lack of clarity on what molecules they screened. I'm told one issue that Moliner et al didn't handle is that the HEK-293 cells they used to measure TrkB binding also express 5-HT receptors, I forget which subtype. Some control conditions to investigate this would be helpful. [...] This is in the category of "I wish someone else would pursue this." Although... it has occurred to it would be conceptually pleasing if the afterglow of MDMA has the same mechanism as the afterglow of classical psychedelics and it involves a simple-ish biological mechanism like this. [...] It'd certainly be a neat story if it works out. The data are the data, but I am skeptical of some parts of their models and interpretation -- a lot hangs on the assumption that the 3H-LSD is really bound to TrkB (at least for the psychedelics part of the story). [...]

[redditn529-1] u/MBaggott (7 January 2024). "[Comment(s)]". Reddit. Retrieved 5 February 2025. I think their first finding, that psychedelics are high affinity TrkB ligands, is simply wrong. They are assuming that HEK293T cells don't naturally express any 5-HT1 receptors, which would be a more plausible explanation for their results. Then their later LSD results use implausibly high concentrations that are unlikely to occur in vivo. I screened some tryptamines with TrkB PAM and agonist assays and did not see anything. [...] I can't explain all their findings. I imagine a lot of things can go wrong when you're measuring something as promiscuous as [3H]LSD. One that I screened was 5-MeO-MiPT, which anecdotally has antidepressant-like effects. It's also worth noting that Bonaventura et al failed to see any interaction of R,R-HNK, the paper's other putative ligand, with TrkB. The literature on TrkB agonists has been confusing since Boltaev et al 2017. Overall, I find a later downstream role for TrkB to be plausible but I've been waiting for someone else to replicate this alleged direct interaction. It should be easy to replicate and extend, yet no one has. [...] N-acetyl-serotonin is also in the category of alleged TrkB ligands people can't replicate. Although there is evidence that some small molecules have BDNF-independent TrkB-mediated effects, I'm not sure there's good evidence that any small molecule really is a TrkB ligand. If we could really repurpose the tryptamine scaffold and screen it against TrkB to get fast acting novel antidepressants, dozens of labs would be doing it and I think we'd already be seeing preprints. So we do need to wait, but the silence is becoming interpretable.

[redditd177-2] u/MBaggott (18 August 2023). "[Comment(s)]". Reddit. Retrieved 5 February 2025. I'm not really a 5-HT2A specialist, but several I know have expressed deep skepticism. Based on this paper, I went ahead and screened 5-MeO-MiPT at TrkB and found it is neither a PAM nor an agonist. So if the theory is correct, it's not true of all psychedelics. If you want a theory for why microdosing might work, the simplest answer may be that both antidepressant and psychedelic effects are mediated by 5-HT2A but that the EC50 for neuroplasticity/antidepressant effects is lower than the EC50 for frank psychedelic effects. I have a commentary piece under review that argues this. This idea is also consistent with Jason Wallach's excellent new preprint. [...] It's not surprising that many therapeutic agents act, at least in part, via TrkB/BDNF pathways. The surprising thing would be if they directly bind to TrkB. Boltaev et al 2017 suggest a lot of findings about direct TrkB stimulation may be wrong. They failed to find agonist or positive allosteric effects for a large number of molecules. [...] For me, direct TrkB interactions are a side quest since they are not relevant to entactogens. However, if you want to set that up, I'd gladly help defray costs and send you some compounds to screen! Yeah, the Boltaev paper is annoying in its lack of clarity on what molecules they screened. I'm told one issue that Moliner et al didn't handle is that the HEK-293 cells they used to measure TrkB binding also express 5-HT receptors, I forget which subtype. Some control conditions to investigate this would be helpful. [...] This is in the category of "I wish someone else would pursue this." Although... it has occurred to it would be conceptually pleasing if the afterglow of MDMA has the same mechanism as the afterglow of classical psychedelics and it involves a simple-ish biological mechanism like this. [...] It'd certainly be a neat story if it works out. The data are the data, but I am skeptical of some parts of their models and interpretation -- a lot hangs on the assumption that the 3H-LSD is really bound to TrkB (at least for the psychedelics part of the story). [...]

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